rs762224063

Positions:

chr7-117587784-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000492.4(CFTR):c.1630G>A(p.Gly544Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,226 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 8.82

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_pathogenic. Variant got 6 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1630G>A	p.Gly544Ser	missense_variant	12/27	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.1630G>A	p.Gly544Ser	missense_variant	12/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250922

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135594

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1460060

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726404

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000336

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces glycine with serine at codon 544 of the CFTR protein (p.Gly544Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs762224063, ExAC 0.05%). This missense change has been observed in individual(s) with cystic fibrosis or infertility (PMID: 10376575, 10923036, 20021716). ClinVar contains an entry for this variant (Variation ID: 555335). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G544S in CFTR (NM_000492.4) has been reported previously in affected individuals with trypisinemia but no elevated sweat chloride as well as infertile men with oligospermia (Scotet V et al,Gallati S et al). The variant has been submitted to ClinVar as Uncertain Significance. The p.G544S variant is observed in an allele frequency of 0.05% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G544S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 544 of CFTR is conserved in all mammalian species. The nucleotide c.1630 in CFTR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2023	The p.G544S variant (also known as c.1630G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1630. The glycine at codon 544 is replaced by serine, an amino acid with similar properties. This alteration was described in the heterozygous state in a newborn with normal sweat test result at birth and four months old (Férec C et al. Hum. Genet., 1995 Nov;96:542-8). This alteration was reported in a male with idiopathic epididymal obstruction in conjunction with the 5T allele; however, the phase was not provided (Mak V et al. JAMA, 1999 Jun;281:2217-24). This alteration was also detected as heterozygous in 1/169 oligospermic men (Gallati S et al. Reprod Biomed Online, 2009 Nov;19:685-94). This amino acid position is highly 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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 08, 2023

Variant summary: CFTR c.1630G>A (p.Gly544Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain and AAA+ ATPase domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251536 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1630G>A has been reported in the literature in individuals affected with cystic fibrosis (Vaidyanathan_2022), neonatal hypertrypsinemia without elevated sweat chloride (Ferec_1995, Scotet_2001) and an infertile male with oligospermia (Gallati_2009). These reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. Co-occurrences with another pathogenic variant has been reported in an individual tested for pancreatitis (SPINK1 c.101A>G, p.N34S). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10376575, 8530001, 20021716, 11168024, 35857025). Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. 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

Natera, Inc.

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;D;.

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

0.69

N;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.4

N;.;N;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.026

D;.;D;.

Sift4G

Uncertain

0.012

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.86

MutPred

0.93

Gain of glycosylation at G544 (P = 0.043);.;.;.;

MVP

0.99

MPC

0.0043

ClinPred

0.37

GERP RS

5.1

Varity_R

0.74

gMVP

0.93

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