7-117531001-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000492.4(CFTR):​c.376G>A​(p.Gly126Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G126D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

10
6
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2O: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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-117531002-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 7-117531001-G-A is Pathogenic according to our data. Variant chr7-117531001-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53808.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.376G>A p.Gly126Ser missense_variant Exon 4 of 27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.376G>A p.Gly126Ser missense_variant Exon 4 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250896
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135580
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:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460062
Hom.:
0
Cov.:
31
AF XY:
0.00000826
AC XY:
6
AN XY:
726414
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:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:1Uncertain:1Other:1
not provided, no classification providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)-- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2021This sequence change replaces glycine with serine at codon 126 of the CFTR protein (p.Gly126Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs397508606, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 19181743, 25042876). This variant is also known as c.508G>A. ClinVar contains an entry for this variant (Variation ID: 53808). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 25042876). This variant disrupts the p.Gly126 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8163293, 10439967, 23974870, 27214204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 21, 2025Variant summary: CFTR c.376G>A (p.Gly126Ser) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250896 control chromosomes (gnomAD). c c.376G>A has been reported in the literature in at least one heterozygous individual affected with congenital bilateral absence of vas deferens (CBAVD), repeated respiratory infections and raised sweat chloride levels without a clinical diagnosis of cystic fibrosis (Sharma_2009). This report, however, does not provide unequivocal conclusions about association of the variant with cystic fibrosis. An experimental study measuring channel function by iodide efflux of the mutant protein compared to WT found to have normal protein maturation process and channel activity (Sharma _2015). However, a recent study conducted by Bihler et al reports approximately 25% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19181743, 25042876, 38388235, 35913788). ClinVar contains an entry for this variant (Variation ID: 53808). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.66
D;.;.;T;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Uncertain
2.5
M;.;.;.;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.6
N;.;.;N;.
REVEL
Pathogenic
0.82
Sift
Benign
0.072
T;.;.;T;.
Sift4G
Pathogenic
0.0
D;.;.;D;.
Polyphen
1.0
D;.;.;.;.
Vest4
0.96
MutPred
0.91
Loss of catalytic residue at I125 (P = 0.2968);Loss of catalytic residue at I125 (P = 0.2968);Loss of catalytic residue at I125 (P = 0.2968);Loss of catalytic residue at I125 (P = 0.2968);Loss of catalytic residue at I125 (P = 0.2968);
MVP
1.0
MPC
0.012
ClinPred
0.72
D
GERP RS
5.7
Varity_R
0.74
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs397508606; hg19: chr7-117171055; API