NM_006005.3:c.647C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006005.3(WFS1):c.647C>G(p.Pro216Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000627 in 1,610,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.97

Publications

4 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)

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18278906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.647C>G	p.Pro216Arg	missense_variant	Exon 6 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.647C>G	p.Pro216Arg	missense_variant	Exon 6 of 8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.647C>G	p.Pro216Arg	missense_variant	Exon 6 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000655

AC:

AN:

244194

AF XY:

0.0000528

show subpopulations

Gnomad AFR exome

AF:

0.000516

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000634

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1458692

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

725334

show subpopulations

African (AFR)

AF:

0.000897

AC:

AN:

33448

American (AMR)

AF:

0.0000449

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85336

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111294

Other (OTH)

AF:

0.000149

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.000236

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000844

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Oct 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: WFS1 c.647C>G (p.Pro216Arg) results in a non-conservative amino acid change located in the Wolframin, EF-hand domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 244194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WFS1 causing Wolfram Syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.647C>G in individuals affected with Wolfram Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 393386). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro216Arg variant in WFS1 has not been previously reported in individuals with hearing loss, Wolfram syndrome, or Wolfram-like disorder. This variant has been identified in 0.07% (5/7552) of African chromosomes and 0.02% (10/497210) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs141233896). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, the clinical si gnificance of the p.Pro216Arg variant is uncertain. -

not provided

Uncertain:1Benign:1

Oct 23, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1

Uncertain:1

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Uncertain:1

Oct 13, 2015

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: PP3, BP4 -

Wolfram syndrome 1

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

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 rs141233896 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

.;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

L;L

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.19

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.12

B;B

Vest4

0.54

MVP

0.99

ClinPred

0.060

GERP RS

3.5

Varity_R

0.056

gMVP

0.64

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over