rs201958172

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000492.4(CFTR):c.358G>A(p.Ala120Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,613,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A120A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:13O:1

Conservation

PhyloP100: 9.52

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a topological_domain Extracellular (size 23) in uniprot entity CFTR_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 7-117530983-G-A is Pathogenic according to our data. Variant chr7-117530983-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53774.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Pathogenic=1, not_provided=1, Likely_pathogenic=2}. Variant chr7-117530983-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.358G>A	p.Ala120Thr	missense_variant	4/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.358G>A	p.Ala120Thr	missense_variant	4/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

250914

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CFTR: PM1, PM2, PM3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2025	Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9272157, 15537723, 11354633, 23951356, 27449771, 19318035, 21520337, 22427236, 9439669, 12752573, 7517264, 21198395, 7513293, 15727251, 23523379, 7532150, 17489851, 11883825, 34426522, 31488014, 33572515, 34405919, 33988008, 34996830, 31990467, 31916691, 34525262, 37313453, 35769956, 18687795, 10439967, 28830496, 36409970, 38388235, 39669589, 37823318) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 22, 2022	The CFTR c.358G>A; p.Ala120Thr variant (rs201958172) has been observed in individuals with cystic fibrosis (CFTR2 database, Chillon 1994, Jalalirad 2004, Padoan 2002, Radivojevic 2004, Sasihuseyinoglu 2019), pancreatitis (Masson 2013), and congenital bilateral absence of vas deferens (Dork 1997). In several individuals with cystic fibrosis, a second pathogenic variant was also identified (Padoan 2002; Sasihuseyinoglu 2019), but a second variant was not reported in many patients carrying p.Ala120Thr. The p.Ala120Thr variant is reported in ClinVar (Variation ID: 53774). The CFTR2 database describes p.Ala120Thr as having varying clinical consequences and those with cystic fibrosis are likely to be pancreatic sufficient (CFTR2 database). This variant is found in the general population with an overall allele frequency of 0.01% (39/282308 alleles) in the Genome Aggregation Database. The alanine at codon 120 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.787). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: CFTR2 database: https://cftr2.org/ Chillon M et al. Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes. Hum Genet. 1994 Apr;93(4):447-51. PMID: 7513293. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. PMID: 9272157. Jalalirad M et al. First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations. J Trop Pediatr. 2004 Dec;50(6):359-61. PMID: 15537723. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Padoan R et al. Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis. Acta Paediatr. 2002;91(1):82-7. PMID: 11883825. Radivojevic D et al. Spectrum of cystic fibrosis mutations in Serbia and Montenegro and strategy for prenatal diagnosis. Genet Test. 2004 Fall;8(3):276-80. PMID: 15727251. Sasihuseyinoglu AS et al. Two years of newborn screening for cystic fibrosis in Turkey: Çukurova experience. Turk J Pediatr. 2019;61(4):505-512. PMID: 31990467. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 21, 2024	The CFTR c.358G>A (p.Ala120Thr) variant has been reported with varying clinical consequences in individuals with cystic fibrosis (PMIDs: 31990467 (2019), 15537723 (2004), 15727251 (2004), 12752573 (2003), 10439967 (1999), 7517264 (1994)), and without cystic fibrosis (PMIDs: 22427236 (2013), 21520337 (2011), 17489851 (2007), 11883825 (2002)). Additionally, this variant has been reported in individuals with pancreatic insufficiency (PMID: 28830496 (2017)), idiopathic chronic pancreatitis (PMID: 23951356 (2013), and congenital absence of the vas deferens (PMID: 9272157 (1997)). The frequency of this variant in the general population, 0.00043 (13/30578 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Therefore, this variant could be a neutral variant or a variant that is associated with CFTR-related disorders. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 14, 2022	- -

Cystic fibrosis

Pathogenic:2Uncertain:3Other:1

Likely pathogenic, flagged submission	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, PM5, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2024	The p.A120T variant (also known as c.358G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 358. The alanine at codon 120 is replaced by threonine, an amino acid with similar properties. This variant was first described in a child with cystic fibrosis (CF) with elevated sweat chloride levels and pancreatic symptoms; however, a second alteration was not identified (Chillón M et al. Hum. Genet., 1994 Apr;93:447-51). This mutation was also detected in an individual with asthma in conjunction with a 5T allele; however, the phase was not provided (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21). A study of individuals with idiopathic chronic pancreatitis identified one individual with this variant and no other alterations in PRSS1, SPINK1, or CTRC genes (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). This variant was also identified in an individual with congenital bilateral absence of the vas deferens (CBAVD); however, a second alteration was not identified (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). The p.A120T variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 15, 2020). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 120 of the CFTR protein (p.Ala120Thr). This variant is present in population databases (rs201958172, gnomAD 0.04%). This missense change has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens or chronic pancreatitis (PMID: 7513293, 7517264, 9272157, 10439967, 18687795, 23951356, 33572515). ClinVar contains an entry for this variant (Variation ID: 53774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	Variant summary: CFTR c.358G>A (p.Ala120Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 1618662 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (6.7e-05 vs 0.013), allowing no conclusion about variant significance. The c.358G>A variant has been reported in the literature in heterozygous or presumed compound heterozygous state in several individuals affected with Non-Classic Cystic Fibrosis (example, Chillon_1994, Kanavakis_2003, Radivojevic_2004), as well as CBAVD, asthma, ICP, and lung disease patients, though full genotype information and sweat test results were often not reported or normal, making interpretation difficult. A few studies reported the variant in compound heterozygosity with a known pathogenic variant (p.F508del) in individuals with intermediate or abnormal sweat chloride test values, with at least one of them affected with pancreatic insufficiency and another one affected with recurrent pneumonia (example, De Wachter_2017, Sasihuiseyinoglu_2019, Munck_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 46.73% of normal chloride channel conductance relative to wild type (example, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31488014, 21198395, 9439669, 7513293, 7517264, 28830496, 9272157, 15537723, 12752573, 10439967, 23951356, 31916691, 11883825, 15727251, 22427236, 31990467, 21520337, 17489851, 11354633, 38388235). ClinVar contains an entry for this variant (Variation ID: 53774). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2024

- -

Infertility disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.;.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.8

L;.;.;.;L

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.012

D;.;.;D;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.90

MutPred

0.87

Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);Gain of disorder (P = 0.1512);

MVP

1.0

MPC

0.010

ClinPred

0.47

GERP RS

5.7

Varity_R

0.69

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over