4-6301941-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_006005.3(WFS1):​c.2146G>C​(p.Ala716Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A716T) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

4
8
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.58
Variant links:
Genes affected
WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-6301941-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WFS1NM_006005.3 linkc.2146G>C p.Ala716Pro missense_variant Exon 8 of 8 ENST00000226760.5 NP_005996.2 O76024A0A0S2Z4V6
WFS1NM_001145853.1 linkc.2146G>C p.Ala716Pro missense_variant Exon 8 of 8 NP_001139325.1 O76024A0A0S2Z4V6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WFS1ENST00000226760.5 linkc.2146G>C p.Ala716Pro missense_variant Exon 8 of 8 1 NM_006005.3 ENSP00000226760.1 O76024

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248846
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135078
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460508
Hom.:
0
Cov.:
99
AF XY:
0.00000138
AC XY:
1
AN XY:
726570
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
D;D
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.86
.;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Uncertain
0.72
D
MutationAssessor
Benign
1.4
L;L
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.3
N;N
REVEL
Pathogenic
0.71
Sift
Benign
0.11
T;T
Sift4G
Benign
0.15
T;T
Polyphen
0.29
B;B
Vest4
0.32
MutPred
0.62
Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);
MVP
1.0
ClinPred
0.41
T
GERP RS
5.5
Varity_R
0.63
gMVP
0.84

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.

Other links and lift over

dbSNP: rs28937893; hg19: chr4-6303668; API