chr4-6301349-G-A

Variant names:

• chr4-6301349-G-A
• rs138232538
• NM_006005.3:c.1554G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM5 PP3 BP4_Strong BP6

The NM_006005.3(WFS1):​c.1554G>A​(p.Met518Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000356 in 1,612,304 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M518K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 7.14
• Publications: 10 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: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301348-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1320487.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, M_CAP, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.022943735).
• BP6: Variant 4-6301349-G-A is Benign according to our data. Variant chr4-6301349-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215358.

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.1554G>A	p.Met518Ile	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1554G>A	p.Met518Ile	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.1554G>A	p.Met518Ile	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1554G>A	p.Met518Ile	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1647G>A	p.Met549Ile	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000491 AC: 123 AN: 250520 AF XY: 0.000406

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1459980 Hom.: 0 Cov.: 99 AF XY: 0.000195 AC XY: 142 AN XY: 726402

African (AFR) AF: 0.00699 AC: 234 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51548

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111986

Other (OTH) AF: 0.000613 AC: 37 AN: 60382

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.00179 AC XY: 133 AN XY: 74476

African (AFR) AF: 0.00652 AC: 271 AN: 41580

American (AMR) AF: 0.000327 AC: 5 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000947 Hom.: 1

Bravo AF: 0.00203

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Monogenic diabetes (1)
-	1	-	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.84
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.70		Loss of methylation at R517 (P = 0.0599)
MVP		0.94
ClinPred		0.063	T
GERP RS		4.4
Varity_R		0.51
gMVP		0.87
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138232538; hg19: chr4-6303076;