4-6288996-C-T

Position:

chr4-6288996-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_006005.3(WFS1):c.325C>T(p.His109Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000734 in 1,608,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H109H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 1.23

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074560344).

BP6

Variant 4-6288996-C-T is Benign according to our data. Variant chr4-6288996-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166570.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}. Variant chr4-6288996-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.325C>T	p.His109Tyr	missense_variant	4/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.325C>T	p.His109Tyr	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.325C>T	p.His109Tyr	missense_variant	4/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

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:

0.0000589

AC:

AN:

237612

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

128700

show subpopulations

Gnomad AFR exome

AF:

0.000600

Gnomad AMR exome

AF:

0.000148

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:

0.0000536

AC:

AN:

1456380

Hom.:

Cov.:

AF XY:

0.0000401

AC XY:

AN XY:

723730

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.000136

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:

0.00000270

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000263

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000938

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

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	This variant is associated with the following publications: (PMID: 12955714) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2013

Variant classified as Uncertain Significance - Favor Benign. The His109Tyr varia nt in WFS1 has not been reported in individuals with hearing loss, but has been identified in 1.0% (2/192) Luhya West African chromosomes by the 1000 Genomes Pr oject and in 0.04% (2/4402) of African American chromosomes by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs112871383). Compu tational analyses (biochemical amino acid properties, conservation, AlignGVGD, P olyPhen2, and SIFT) suggest that the His109Tyr variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. I n summary, the clinical significance of this variant cannot be determined with c ertainty; however based upon its presence in the general population and the comp utational data, we would lean towards a more likely benign role. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 01, 2017

ACMG Criteria:PP3 (6 predictors), BP4 (3 predictors) -

Wolfram syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs112871383 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.80

.;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.075

T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.77

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.38

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.022

B;B

Vest4

0.37

MVP

1.0

ClinPred

0.018

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.58

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