rs200135768

Variant names:

• chr4-6277682-G-T
• rs200135768
• NM_006005.3:c.227G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-6277682-G-T
• chr4-6277682-G-A
• chr4-6277682-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006005.3(WFS1):​c.227G>T​(p.Gly76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,558,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. G76S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.134
• Publications: 4 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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038545728).
• BP6: Variant 4-6277682-G-T is Benign according to our data. Variant chr4-6277682-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215375.

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.227G>T	p.Gly76Val	missense	Exon 2 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.227G>T	p.Gly76Val	missense	Exon 2 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.227G>T	p.Gly76Val	missense	Exon 2 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.227G>T	p.Gly76Val	missense	Exon 2 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.227G>T	p.Gly76Val	missense	Exon 2 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152262 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00639

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: 0.00143

GnomAD2 exomes AF: 0.000438 AC: 70 AN: 159990 AF XY: 0.000419

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.000389

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000324

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000190 AC: 267 AN: 1406468 Hom.: 0 Cov.: 33 AF XY: 0.000183 AC XY: 127 AN XY: 694430

African (AFR) AF: 0.00680 AC: 218 AN: 32052

American (AMR) AF: 0.000353 AC: 13 AN: 36876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25262

East Asian (EAS) AF: 0.00 AC: 0 AN: 36560

South Asian (SAS) AF: 0.00 AC: 0 AN: 79824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4934

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084190

Other (OTH) AF: 0.000549 AC: 32 AN: 58274

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152380 Hom.: 0 Cov.: 34 AF XY: 0.00174 AC XY: 130 AN XY: 74512

African (AFR) AF: 0.00637 AC: 265 AN: 41592

American (AMR) AF: 0.000327 AC: 5 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00199

ESP6500AA AF: 0.00586 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000327 AC: 37

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Monogenic diabetes (1)
-	-	1	WFS1-related disorder (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	3.8
DANN	Benign	0.75
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.13
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.18
Sift	Benign	0.24	T
Sift4G	Benign	0.15	T
Polyphen		0.078	B
Vest4		0.18
MVP		0.65
ClinPred		0.0039	T
GERP RS		0.29
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.030
gMVP		0.33
Mutation Taster		=96/4	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: rs200135768; hg19: chr4-6279409;