Genetic Variant WFS1:p.Pro7Pro (chr4-6277476-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006005.3(WFS1):c.21G>T(p.Pro7Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,557,912 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 6 hom., cov: 34)

Exomes 𝑓: 0.0022 ( 97 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.28

Publications

2 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):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Wolfram-like syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-6277476-G-T is Benign according to our data. Variant chr4-6277476-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.28 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00129 (197/152316) while in subpopulation SAS AF = 0.0379 (183/4830). AF 95% confidence interval is 0.0334. There are 6 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.21G>T	p.Pro7Pro	synonymous	Exon 2 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.21G>T	p.Pro7Pro	synonymous	Exon 2 of 8	NP_001139325.1	O76024

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WFS1	ENST00000226760.5	TSL:1 MANE Select	c.21G>T	p.Pro7Pro	synonymous	Exon 2 of 8	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.21G>T	p.Pro7Pro	synonymous	Exon 2 of 8	ENSP00000423337.1	O76024
WFS1	ENST00000852027.1		c.21G>T	p.Pro7Pro	synonymous	Exon 2 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0387

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00572

AC:

920

AN:

160838

AF XY:

0.00758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000324

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000646

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.00225

AC:

3159

AN:

1405596

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2224

AN XY:

693924

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32108

American (AMR)

AF:

0.0000821

AC:

AN:

36558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25228

East Asian (EAS)

AF:

0.000301

AC:

AN:

36602

South Asian (SAS)

AF:

0.0364

AC:

2907

AN:

79824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48408

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

1082936

Other (OTH)

AF:

0.00338

AC:

197

AN:

58260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00129

AC:

197

AN:

152316

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0379

AC:

183

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000981

Hom.:

Bravo

AF:

0.000223

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Autosomal dominant nonsyndromic hearing loss 6 (1)

WFS1-Related Spectrum Disorders (1)

Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.56

(source)

DANN

Benign

0.76

PhyloP100

-2.3

PromoterAI

-0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over