7-117559476-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):ā€‹c.1405A>Gā€‹(p.Met469Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,603,778 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 Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

9
6
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 8.79
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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.976
PP5
Variant 7-117559476-A-G is Pathogenic according to our data. Variant chr7-117559476-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFTRNM_000492.4 linkc.1405A>G p.Met469Val missense_variant 11/27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730
CFTR-AS1NR_149084.1 linkn.221+1257T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.1405A>G p.Met469Val missense_variant 11/271 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152126
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251258
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000620
AC:
9
AN:
1451652
Hom.:
0
Cov.:
28
AF XY:
0.00000830
AC XY:
6
AN XY:
723006
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000758
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000363
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74326
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000192
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 09, 2024Variant summary: CFTR c.1405A>G (p.Met469Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251258 control chromosomes (gnomAD). c.1405A>G has been reported in the literature and CFTR databases in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD) or obstructive azoospermia (e.g. Lu_2013, Lu_2014, Fang_2022, SickKids CFTR database, CFTR-France). It has also been reported in the heterozygous state in an individual with chronic pancreatitis, without strong evidence for causality (Xiao_2017) and together with F508del in a CF patient (Sachdeva_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Bergougnoux_2023). The results indicate that the variant negatively affects protein folding and has only minor CFTR channel function, with approximately 10-15% activity versus WT CFTR. The following publications have been ascertained in the context of this evaluation (PMID: 29173301, 36567205, 36437957, 24559724, 23953609, 22299590). ClinVar contains an entry for this variant (Variation ID: 53248). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 22, 2021- -
Cystic fibrosis Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2025This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 469 of the CFTR protein (p.Met469Val). This variant is present in population databases (rs397508203, gnomAD 0.01%). This missense change has been observed in individual(s) with azoospermia, clinical features of cystic fibrosis, and/or congenital absence of the vas deferens (CAVD) (PMID: 22299590, 23953609, 24559724, 35913788, 36437957). ClinVar contains an entry for this variant (Variation ID: 53248). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 36567205). This variant disrupts the p.Met469 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 30811104), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided, no classification providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)-- -
Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submittercurationCFTR-FranceMar 26, 2018the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.;.;D;.
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Benign
1.7
L;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-2.1
N;.;.;N;.
REVEL
Pathogenic
0.87
Sift
Benign
0.056
T;.;.;T;.
Sift4G
Uncertain
0.0030
D;.;.;D;.
Polyphen
1.0
D;.;.;.;.
Vest4
0.94
MutPred
0.90
Gain of ubiquitination at K464 (P = 0.115);.;.;.;.;
MVP
1.0
MPC
0.0041
ClinPred
0.66
D
GERP RS
5.5
Varity_R
0.83
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs397508203; hg19: chr7-117199530; API