NM_006005.3:c.577A>C

Variant names:

• chr4-6291313-A-C
• rs41264699
• NM_006005.3:c.577A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006005.3(WFS1):​c.577A>C​(p.Lys193Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,240 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K193R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17
• Conservation: PhyloP100: 5.20
• Publications: 25 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01354751).
• BP6: Variant 4-6291313-A-C is Benign according to our data. Variant chr4-6291313-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00382 (5578/1461340) while in subpopulation SAS AF = 0.0119 (1026/86258). AF 95% confidence interval is 0.0113. There are 28 homozygotes in GnomAdExome4. There are 2973 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 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.577A>C	p.Lys193Gln	missense	Exon 5 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.577A>C	p.Lys193Gln	missense	Exon 5 of 8	NP_001139325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.577A>C	p.Lys193Gln	missense	Exon 5 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.577A>C	p.Lys193Gln	missense	Exon 5 of 8	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.577A>C	p.Lys193Gln	missense	Exon 5 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 405 AN: 151782 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000654

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00545

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00834

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00380 AC: 951 AN: 250524 AF XY: 0.00437

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00382 AC: 5578 AN: 1461340 Hom.: 28 Cov.: 35 AF XY: 0.00409 AC XY: 2973 AN XY: 726938

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0119 AC: 1026 AN: 86258

European-Finnish (FIN) AF: 0.000870 AC: 46 AN: 52876

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00351 AC: 3905 AN: 1112006

Other (OTH) AF: 0.00344 AC: 208 AN: 60392

GnomAD4 genome AF: 0.00265 AC: 403 AN: 151900 Hom.: 1 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74212

African (AFR) AF: 0.000652 AC: 27 AN: 41406

American (AMR) AF: 0.00544 AC: 83 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00793 AC: 38 AN: 4790

European-Finnish (FIN) AF: 0.000474 AC: 5 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 67972

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00346 Hom.: 5

Bravo AF: 0.00250

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00401 AC: 487

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00409

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	4	not specified (4)
-	-	2	Autosomal dominant nonsyndromic hearing loss 6 (2)
-	-	1	Monogenic diabetes (1)
-	-	1	Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	-	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.69
Sift	Benign	0.052	T
Sift4G	Benign	0.082	T
Polyphen		0.91	P
Vest4		0.69
MVP		1.0
ClinPred		0.031	T
GERP RS		3.4
Varity_R		0.19
gMVP		0.78
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs41264699; hg19: chr4-6293040; COSMIC: COSV107315701; COSMIC: COSV107315701;