NM_006005.3:c.1820C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_006005.3(WFS1):​c.1820C>A​(p.Pro607His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P607R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

11
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.97

Publications

0 publications found
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]
WFS1 Gene-Disease associations (from GenCC):
  • Wolfram-like syndrome
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
  • Wolfram syndrome
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • autosomal dominant nonsyndromic hearing loss 6
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • cataract 41
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Wolfram syndrome 1
    Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • early-onset nuclear cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • type 2 diabetes mellitus
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-6301615-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1297726.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WFS1NM_006005.3 linkc.1820C>A p.Pro607His missense_variant Exon 8 of 8 ENST00000226760.5 NP_005996.2 O76024A0A0S2Z4V6
WFS1NM_001145853.1 linkc.1820C>A p.Pro607His 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.1820C>A p.Pro607His missense_variant Exon 8 of 8 1 NM_006005.3 ENSP00000226760.1 O76024

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461800
Hom.:
0
Cov.:
99
AF XY:
0.00000138
AC XY:
1
AN XY:
727210
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53366
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111988
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.81
.;T
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
7.0
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0040
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.88
MutPred
0.90
Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP
1.0
ClinPred
0.98
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.47
gMVP
0.94
Mutation Taster
=7/93
disease causing

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

Other links and lift over

dbSNP: rs373862003; hg19: chr4-6303342; API