rs55814513

Variant names:

• chr4-6301470-G-A
• rs55814513
• NM_006005.3:c.1675G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6301470-G-A
• chr4-6301470-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PM1 PM5 BP4_Strong BP6_Very_Strong BS2

The NM_006005.3(WFS1):​c.1675G>A​(p.Ala559Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00485 in 1,612,772 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A559V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0050 (20 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 5.49
• Publications: 28 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 -12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_006005.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301471-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2734643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010330886).
• BP6: Variant 4-6301470-G-A is Benign according to our data. Variant chr4-6301470-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.1675G>A	p.Ala559Thr	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1675G>A	p.Ala559Thr	missense	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.1675G>A	p.Ala559Thr	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1675G>A	p.Ala559Thr	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1768G>A	p.Ala590Thr	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152250 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00561

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00396 AC: 992 AN: 250512 AF XY: 0.00399

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00574

Gnomad NFE exome AF: 0.00584

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00501 AC: 7318 AN: 1460404 Hom.: 20 Cov.: 100 AF XY: 0.00496 AC XY: 3604 AN XY: 726634

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.00152 AC: 68 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00371 AC: 320 AN: 86248

European-Finnish (FIN) AF: 0.00591 AC: 307 AN: 51970

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00570 AC: 6335 AN: 1112002

Other (OTH) AF: 0.00397 AC: 240 AN: 60382

GnomAD4 genome AF: 0.00335 AC: 511 AN: 152368 Hom.: 0 Cov.: 34 AF XY: 0.00314 AC XY: 234 AN XY: 74502

African (AFR) AF: 0.000962 AC: 40 AN: 41592

American (AMR) AF: 0.00131 AC: 20 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00561 AC: 382 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00433 Hom.: 2

Bravo AF: 0.00303

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00451 AC: 548

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	4	not specified (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Monogenic diabetes (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.00053
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.41
Sift	Benign	0.37	T
Sift4G	Benign	0.73	T
Polyphen		0.43	B
Vest4		0.16
MVP		0.95
ClinPred		0.0083	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.69
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: rs55814513; hg19: chr4-6303197;