4-6270099-T-C

Variant names:

• chr4-6270099-T-C
• rs6830765
• NM_006005.3:c.-6+85T>C

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.-6+85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,706 control chromosomes in the GnomAD database, including 26,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26643 hom., cov: 34)
  • Exomes 𝑓: 0.58 (24 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.596
• Publications: 17 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=-1.02).
• BP6: Variant 4-6270099-T-C is Benign according to our data. Variant chr4-6270099-T-C is described in ClinVar as [Benign]. Clinvar id is 1292283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.-6+85T>C		intron_variant	Intron 1 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.-2+85T>C		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.-6+85T>C		intron_variant	Intron 1 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88648 AN: 151480 Hom.: 26620 Cov.: 34

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.608

GnomAD4 exome AF: 0.576 AC: 68 AN: 118 Hom.: 24 AF XY: 0.563 AC XY: 54 AN XY: 96

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 1.00 AC: 4 AN: 4

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.538 AC: 56 AN: 104

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.585 AC: 88710 AN: 151588 Hom.: 26643 Cov.: 34 AF XY: 0.589 AC XY: 43643 AN XY: 74106

African (AFR) AF: 0.518 AC: 21309 AN: 41166

American (AMR) AF: 0.663 AC: 10114 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2310 AN: 3466

East Asian (EAS) AF: 0.934 AC: 4804 AN: 5146

South Asian (SAS) AF: 0.670 AC: 3222 AN: 4810

European-Finnish (FIN) AF: 0.550 AC: 5800 AN: 10552

Middle Eastern (MID) AF: 0.608 AC: 175 AN: 288

European-Non Finnish (NFE) AF: 0.579 AC: 39280 AN: 67882

Other (OTH) AF: 0.610 AC: 1283 AN: 2104

Alfa AF: 0.581 Hom.: 3202

Bravo AF: 0.590

Asia WGS AF: 0.770 AC: 2669 AN: 3466

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	-1.0
CADD	Benign	6.8
DANN	Benign	0.32
PhyloP100		-0.60
PromoterAI		-0.014	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: rs6830765; hg19: chr4-6271826;