NM_006005.3:c.985T>A

Variant names:

• chr4-6300780-T-A
• rs188848517
• NM_006005.3:c.985T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_006005.3(WFS1):​c.985T>A​(p.Phe329Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F329F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.78
• Publications: 7 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):

• 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)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 20 uncertain in NM_006005.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

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.985T>A	p.Phe329Ile	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.985T>A	p.Phe329Ile	missense	Exon 8 of 8	NP_001139325.1	O76024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.985T>A	p.Phe329Ile	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.985T>A	p.Phe329Ile	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1078T>A	p.Phe360Ile	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251470 AF XY: 0.000177

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727212

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86252

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1111952

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74408

African (AFR) AF: 0.000120 AC: 5 AN: 41532

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000164 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	1	-	not specified (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.81
Sift	Benign	0.031	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.78
MVP		1.0
ClinPred		0.097	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.89
Mutation Taster		=2/98	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

Other links and lift over

dbSNP: rs188848517; hg19: chr4-6302507;