chr4-6302000-C-T

Variant names:

• chr4-6302000-C-T
• rs71530911
• NM_006005.3:c.2205C>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.2205C>T​(p.Tyr735Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,612,654 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00049 (2 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0740
• Publications: 5 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-6302000-C-T is Benign according to our data. Variant chr4-6302000-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.074 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00274 (418/152358) while in subpopulation AFR AF = 0.00844 (351/41586). AF 95% confidence interval is 0.00771. There are 5 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2205C>T	p.Tyr735Tyr	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.2205C>T	p.Tyr735Tyr	synonymous	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.2205C>T	p.Tyr735Tyr	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.2205C>T	p.Tyr735Tyr	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.2298C>T	p.Tyr766Tyr	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152240 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00100 AC: 247 AN: 245898 AF XY: 0.000791

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000490 AC: 715 AN: 1460296 Hom.: 2 Cov.: 98 AF XY: 0.000472 AC XY: 343 AN XY: 726444

African (AFR) AF: 0.00863 AC: 289 AN: 33472

American (AMR) AF: 0.00152 AC: 68 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52132

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111856

Other (OTH) AF: 0.00149 AC: 90 AN: 60358

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152358 Hom.: 5 Cov.: 34 AF XY: 0.00285 AC XY: 212 AN XY: 74508

African (AFR) AF: 0.00844 AC: 351 AN: 41586

American (AMR) AF: 0.00196 AC: 30 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68032

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00304

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.9
DANN	Benign	0.93
PhyloP100		0.074
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs71530911; hg19: chr4-6303727; COSMIC: COSV56989264; COSMIC: COSV56989264;