rs148783445

Positions:

chr7-117666998-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000492.4(CFTR):c.4333G>A(p.Asp1445Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: 9.12

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02589032).

BP6

Variant 7-117666998-G-A is Benign according to our data. Variant chr7-117666998-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53941.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4333G>A	p.Asp1445Asn	missense_variant	27/27	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.4333G>A	p.Asp1445Asn	missense_variant	27/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000737

AC:

112

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000335

AC:

AN:

250898

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000169

AC:

247

AN:

1461724

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152148

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.00100

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	The CFTR c.4333G>A; p.Asp1445Asn variant (rs148783445) is reported in the medical literature in individuals affected with cystic fibrosis or other CFTR-related disorders, but without clear association with disease (Castellani 2017, Claustres 2000, Keiles 2006, Masson 2013, Mieusset 2020, Picca 2010, Schrijver 2005, Zeiger 2020). This variant is reported in ClinVar (Variation ID: 53941), and is found in the general population with an overall allele frequency of 0.04% (106/282286 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1445 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.537). However, given the lack of specific clinical and functional data, the significance of the p.Asp1445Asn variant is uncertain at this time. References: Castellani C et al. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. Arch Dis Child. 2017 Jul;102(7):644-646. PMID: 26755536. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. 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. 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; 8(8): e73522. PMID: 23951356. Mieusset R et al. Male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. Andrology. 2020 May;8(3):645-653. PMID: 31872980. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. PMID: 19897426. Schrijver I et al. Diagnostic Testing by CFTR Gene Mutation Analysis in a Large Group of Hispanics. J Mol Diagn. 2005 May; 7(2): 289–299. PMID: 15858154. Zeiger AM et al. Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico. Pediatr Pulmonol. 2020 Feb;55(2):533-540. PMID: 31665830. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Observed in individuals with cystic fibrosis and other CFTR-related disorders, without a second CFTR variant reported (Claustres 2000, Schrijver 2005, Keiles 2006, Trujillano 2015); Observed with a pathogenic variant, phase unknown, in an infant without cystic fibrosis and a normal sweat chloride result (Castellani 2017); Published functional studies are inconclusive: normal interaction with AMPK, the clinical significance of which is unknown (Hallows 2000); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 15858154, 17003641, 10923036, 26436105, 22995991, 23951356, 25735457, 19897426, 26847993, 10862786, 32357917, 26755536, 20722470, 34426522, 33946859, 31665830, 31682332, 34996830, 32819855) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 23, 2023	The variant has been reported in a child with an elevated sweat chloride test, chronic cough, and pancreatic insufficiency; a second CFTR variant was not identified. The frequency of this variant in the general population, 0.002 (50/24958 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with CF (PMIDs: 10923036 (2000), 15858154 (2005), 32819855 (2020), 36409994 (2022)), pancreatitis (PMIDs: 17003641 (2006), 23951356 (2013)), pulmonary disease (PMIDs: 20722470 (2010), 33432171 (2021), 34996830 (2022)), and infertility (PMIDs: 31872980 (2020), 32357917 (2020)). One functional study in yeast has shown that this variant does not interfere with AMPK interaction (PMID: 10862786 (2000)), however further research is needed. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2022	- -

Cystic fibrosis

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 22, 2019	This CFTR variant has been previously identified in patients with features of cystic fibrosis, but also in one infant with a normal sweat chloride concentration. The clinical significance of this variant is classified as uncertain by multiple submitters in ClinVar. CFTR c.4333G>A (rs148783445) has been identified in a large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African subpopulation (gnomAD: 50/24958 alleles; 0.02%, no homozygotes). Of three bioinformatics tools queried, two predict that the substitution would be possibly damaging, while one predicts that it would be tolerated. The aspartic acid residue at this position is conserved across many, but not all of the species assessed. We consider the clinical significance of c.4333G>A to be uncertain at this time. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 08, 2023

Variant summary: CFTR c.4333G>A (p.Asp1445Asn) results in a conservative amino acid change in 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 0.00034 in 251444 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00034 vs 0.013), allowing no conclusion about variant significance. c.4333G>A has been reported in the literature in individuals affected with or suspected to exhibit symptoms of Cystic Fibrosis and Cystic Fibrosis related disorders (e.g. Claustres_2000, Schrijver_2005, Trujilliano_2015, Zeigler_2020, da Silva Filho_2020). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant has also been reported in compound heterozygosity with a well-known pathogenic mutation (CFTR F508del) in at least one infant who had a normal sweat chloride test (Castellani_2016). In addition, the variant has been reported in individuals affected with pancreatitis (Keiles_2006, Masson_2013), sarcoidosis (Makrythanasis_2010), and congenital unilateral absence of vas deferens (CUAVD; Mieusset_2019), but without strong evidence for causality. One publication reports experimental evidence indicating that the variant does not disrupt interactions with AMPK in a yeast-based assay (Hallows_2000), however the clinical significance of this finding is not clear. The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 26755536, 32357917, 10923036, 10862786, 17003641, 26847993, 20722470, 26354092, 23951356, 31872980, 19897426, 15858154, 31682332, 26436105, 31665830, 32819855). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as uncertain significance and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

The CFTR c.4333G>A variant is predicted to result in the amino acid substitution p.Asp1445Asn. This variant has been reported in individuals with cystic fibrosis or other CFTR-related disorders, although it is unclear if a second CFTR variant was present or if zygosity was known (Claustres et al. 2000. PubMed ID: 10923036; Schrijver et al. 2005. PubMed ID: 15858154; Trujilliano et al. 2015. PubMed ID: 26436105; da Silva Filho et al. 2020. PubMed ID: 32819855; Zeigler et al. 2020. PubMed ID: 31665830). This variant has been reported in the heterozygous state in individuals with pancreatitis, without additional evidence to support its pathogenicity (Keiles et al. 2006. PubMed ID: 17003641; Masson et al. 2013. PubMed ID: 23951356). This variant has also been reported in an individual who had a normal sweat chloride test and also carried the common, pathogenic CFTR c.1521_1523delCTT (p.Phe508del) variant (Castellani et al. 2016. PubMed ID: 26755536). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.97

N;N;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.012

D;D;.

Polyphen

0.97

D;.;.

Vest4

0.25

MVP

0.99

MPC

0.0042

ClinPred

0.069

GERP RS

5.5

Varity_R

0.38

gMVP

0.52

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