4-6301595-C-T

Variant names:

• chr4-6301595-C-T
• rs71524362
• NM_006005.3:c.1800C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006005.3(WFS1):​c.1800C>T​(p.Thr600Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,148 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T600T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (28 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.917
• Publications: 1 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)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-6301595-C-T is Benign according to our data. Variant chr4-6301595-C-T is described in ClinVar as Benign. ClinVar VariationId is 137916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.917 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1572/152334) while in subpopulation AFR AF = 0.0348 (1446/41572). AF 95% confidence interval is 0.0333. There are 27 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.1800C>T	p.Thr600Thr	synonymous	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.1800C>T	p.Thr600Thr	synonymous	Exon 8 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.1800C>T	p.Thr600Thr	synonymous	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.1800C>T	p.Thr600Thr	synonymous	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.1893C>T	p.Thr631Thr	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1571 AN: 152216 Hom.: 27 Cov.: 34

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00307 AC: 771 AN: 251414 AF XY: 0.00239

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00132 AC: 1932 AN: 1461814 Hom.: 28 Cov.: 100 AF XY: 0.00118 AC XY: 858 AN XY: 727216

African (AFR) AF: 0.0384 AC: 1287 AN: 33478

American (AMR) AF: 0.00427 AC: 191 AN: 44720

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

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000223 AC: 248 AN: 1111990

Other (OTH) AF: 0.00267 AC: 161 AN: 60392

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152334 Hom.: 27 Cov.: 34 AF XY: 0.00998 AC XY: 743 AN XY: 74486

African (AFR) AF: 0.0348 AC: 1446 AN: 41572

American (AMR) AF: 0.00562 AC: 86 AN: 15308

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

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68038

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.0118

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.63
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs71524362; hg19: chr4-6303322;