4-6277320-C-T

Variant names:

• chr4-6277320-C-T
• rs10937714
• NM_006005.3:c.-5-131C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.-5-131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 866,530 control chromosomes in the GnomAD database, including 282,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50814 hom., cov: 34)
  • Exomes 𝑓: 0.80 (232084 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.899
• Publications: 12 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 (BayesDel_noAF=-0.92).
• BP6: Variant 4-6277320-C-T is Benign according to our data. Variant chr4-6277320-C-T is described in ClinVar as Benign. ClinVar VariationId is 1257985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.-5-131C>T		intron_variant	Intron 1 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.-1-135C>T		intron_variant	Intron 1 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.-5-131C>T		intron_variant	Intron 1 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.815 AC: 124027 AN: 152098 Hom.: 50767 Cov.: 34

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.838

GnomAD4 exome AF: 0.804 AC: 574508 AN: 714314 Hom.: 232084 AF XY: 0.804 AC XY: 299047 AN XY: 371774

African (AFR) AF: 0.831 AC: 15565 AN: 18738

American (AMR) AF: 0.878 AC: 29603 AN: 33700

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 16005 AN: 18700

East Asian (EAS) AF: 0.968 AC: 31613 AN: 32668

South Asian (SAS) AF: 0.817 AC: 47918 AN: 58682

European-Finnish (FIN) AF: 0.758 AC: 34401 AN: 45358

Middle Eastern (MID) AF: 0.846 AC: 2448 AN: 2892

European-Non Finnish (NFE) AF: 0.786 AC: 368249 AN: 468226

Other (OTH) AF: 0.812 AC: 28706 AN: 35350

GnomAD4 genome AF: 0.816 AC: 124133 AN: 152216 Hom.: 50814 Cov.: 34 AF XY: 0.815 AC XY: 60608 AN XY: 74406

African (AFR) AF: 0.833 AC: 34606 AN: 41530

American (AMR) AF: 0.859 AC: 13156 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 2934 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4876 AN: 5164

South Asian (SAS) AF: 0.823 AC: 3968 AN: 4824

European-Finnish (FIN) AF: 0.752 AC: 7974 AN: 10600

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.792 AC: 53835 AN: 67996

Other (OTH) AF: 0.838 AC: 1774 AN: 2116

Alfa AF: 0.791 Hom.: 4855

Bravo AF: 0.825

Asia WGS AF: 0.879 AC: 3057 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.50
PhyloP100		-0.90
PromoterAI		-0.0033	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs10937714; hg19: chr4-6279047;