rs121909021

Positions:

chr7-117540276-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP5_Strong

The NM_000492.4(CFTR):c.1046C>T(p.Ala349Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:14

Conservation

PhyloP100: 7.43

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 8 ACMG points.

PM1

In a transmembrane_region Helical; Name=6 (size 18) in uniprot entity CFTR_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117540276-C-T is Pathogenic according to our data. Variant chr7-117540276-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 7172.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=14, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1046C>T	p.Ala349Val	missense_variant	8/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1046C>T	p.Ala349Val	missense_variant	8/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152110

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

251102

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000308

AC:

450

AN:

1461564

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

190

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000374

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000138

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74294

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The CFTR c.1046C>T; p.Ala349Val variant has been reported in patients diagnosed with congenital bilateral absence of vas deferens (Dayangac 2004) or pancreatitis (Keiles 2006), when found in-trans with pathogenic CFTR variants (Dayangac 2004). Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). The observed variant has been submitted to ClinVar with conflicting interpretation of pathogenicity (Pathogenic/Likely Pathogenic/ Variant of Uncertain Significance). The p.Ala349Val variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 349 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Ala349Val in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. According to Cystic fibrosis mutation database, the effect of homozygous mutation on this disorder is uncertain, hence the variant has been classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 349 of the CFTR protein (p.Ala349Val). This variant is present in population databases (rs121909021, gnomAD 0.02%). This missense change has been observed in individuals with CFTR-related diseases, including recurrent pancreatitis, cystic fibrosis (CF), CF-related metabolic syndrome, and congenital bilateral absence of the vas deferens (PMID: 15070876, 15638824, 17003641, 22094894, 25754095, 26671754). ClinVar contains an entry for this variant (Variation ID: 7172). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 30046002). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 22, 2020	CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information. -
Uncertain significance, reviewed by expert panel	research	CFTR2	Oct 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2023	The p.A349V variant (also known as c.1046C>T), located in coding exon 8 of the CFTR gene, results from a C to T substitution at nucleotide position 1046. The alanine at codon 349 is replaced by valine, an amino acid with similar properties. This variant was identified in one individual with congenital bilateral absence of the vas deferens (CBAVD) and one individual with recurrent acute pancreatitis; both individuals were also heterozygous for a pathogenic mutation, but the phase is unknown (Dayangaç D et al. Hum. Reprod., 2004 May;19:1094-100; Sultan M et al. J. Pediatr. Gastroenterol. Nutr., 2012 May;54:645-50). In CFBE cells, this variant demonstrated 45% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). 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 available evidence to date, the clinical significance of this alteration remains unclear. -

not provided

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34405919, 8627844, 11933191, 16635477, 15024729, 19324992, 25304080, 25735457, 33500538, 30046002, 7683952, 17003641, 31036917, 25087612, 26671754, 23523379, 25754095, 11168024, 15070876, 15638824, 20100616, 22094894, 29669919, 30888834, 33922413, 19897426, 34996830, 35652053, 36253274, 37873426, 29805046) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2023	This variant has been reported in the published literature in individuals with pancreatic sufficient cystic fibrosis (PMID: 25754095 (2015)), pancreatitis (PMID: 17003641 (2006), 22094894 (2012)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 8627844 (1996), 15070876 (2004)), and CFTR-related metabolic syndrome (CRMS) (PMID: 26671754 (2016)). A functional assay found this variant showed decreased CFTR function compared to wild-type (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.00022 (28/128882 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2023	The CFTR c.1046C>T; p.Ala349Val variant (rs121909021) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (Dayangac 2004, Havasi 2010) or pancreatitis (Keiles 2006, Sultan 2010), when found in-trans with pathogenic CFTR variants (Dayangac 2004, Sultan 2012). Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). This variant is reported in ClinVar (Variation ID: 7172). It is found in the general population with an overall allele frequency of 0.01% (32/282468 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.632). Due to its reported occurrence in CFTR-related disorders, the p.Ala349Val variant is classified as mildly pathogenic. References: Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. PMID: 15070876. Havasi V et al. Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. Fertil Steril. 2010 Nov;94(6):2122-7. PMID: 20100616. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 May;54(5):645-50. PMID: 22094894. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 23, 2024

Variant summary: CFTR c.1046C>T (p.Ala349Val) results in a non-conservative amino acid change located in the ABC transporter transmembrane region 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 0.00011 in 251726 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00011 vs 0.013), allowing no conclusion about variant significance. c.1046C>T has been reported in the literature as a non-informative genotype in individuals ranging from a healthy carrier male, CBAVD, laboratory based CF genotyping cohorts, pancreatitis, pancreatically sufficient CF and cystic fibrosis transmembrane regulator-related metabolic syndrome with normal sweat chloride levels (example, Audrezet_1993, Schlegel_1996, Scotet_2001, Ravnik-Glavac_2002, Castaldo_2005, Lucarelli_2006, Sultan_2012, Wooldridge_2015, Schwartz_2009, Havasi_2010, Keiles_2006, Levy_2016, Tamura_2018, McCague_2019). In our conservative assessment, these data do not allow any conclusion about variant significance. Two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. The most pronounced variant effect results in 30%-50% of normal CFTR activity with a categorization as indeterminate (Raraigh_2018, Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11168024, 17003641, 15638824, 19324992, 11933191, 7683952, 16635477, 8627844, 22094894, 20100616, 25735457, 25754095, 29805046, 30046002, 29669919, 26671754, 30888834). ClinVar contains an entry for this variant (Variation ID: 7172). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Apr 21, 2023

- -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;.;.;T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

0.20

N;.;.;.;N

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.23

N;.;.;N;.

REVEL

Uncertain

0.63

Sift

Benign

0.17

T;.;.;T;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

0.91

P;.;.;.;.

Vest4

0.49

MVP

1.0

MPC

0.0064

ClinPred

0.54

GERP RS

5.3

Varity_R

0.42

gMVP

0.81

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