rs200815431

Variant names:

• chr16-79211747-C-T
• rs200815431
• NM_016373.4:c.1196C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-79211747-C-T
• chr16-79211747-C-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_016373.4(WWOX):​c.1196C>T​(p.Ala399Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A399T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.47
• Publications: 8 publications found

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

MAF (HGNC:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

MAF Gene-Disease associations (from GenCC):

• Ayme-Gripp syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract 21 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fine-Lubinsky syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261722 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.027652591).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000322 (49/152294) while in subpopulation AFR AF = 0.000722 (30/41580). AF 95% confidence interval is 0.000518. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. 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
	WWOX	NM_016373.4	MANE Select	c.1196C>T	p.Ala399Val	missense	Exon 9 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.857C>T	p.Ala286Val	missense	Exon 8 of 8	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1196C>T	p.Ala399Val	missense	Exon 9 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000406884.6	TSL:1	c.656C>T	p.Ala219Val	missense	Exon 6 of 6	ENSP00000384495.2	Q9NZC7-5
	WWOX	ENST00000402655.6	TSL:1	c.549C>T	p.Gly183Gly	synonymous	Exon 5 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000204 AC: 51 AN: 249462 AF XY: 0.000222

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461884 Hom.: 0 Cov.: 88 AF XY: 0.000118 AC XY: 86 AN XY: 727244

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000629 AC: 70 AN: 1112006

Other (OTH) AF: 0.000248 AC: 15 AN: 60396

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74466

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.000720 AC: 11 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.00100 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.4
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.85	T
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.093	B
Vest4		0.12
MVP		0.83
ClinPred		0.011	T
GERP RS		-5.9
Varity_R		0.035
gMVP		0.40
Mutation Taster		=93/7	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: rs200815431; hg19: chr16-79245644; COSMIC: COSV68354119; COSMIC: COSV68354119;