rs1076514

Variant names:

• chr16-78125135-G-A
• rs1076514
• NM_016373.4:c.409+9981G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016373.4(WWOX):​c.409+9981G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,070 control chromosomes in the GnomAD database, including 7,268 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7268 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.799
• Publications: 6 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]

WWOX Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 12

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.409+9981G>A		intron_variant	Intron 4 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.70+9981G>A		intron_variant	Intron 3 of 7		NP_001278926.1
WWOX	NM_130791.5	c.409+9981G>A		intron_variant	Intron 4 of 5		NP_570607.1
WWOX	NR_120436.3	n.648+9981G>A		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.409+9981G>A		intron_variant	Intron 4 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45458 AN: 151952 Hom.: 7260 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45494 AN: 152070 Hom.: 7268 Cov.: 32 AF XY: 0.298 AC XY: 22164 AN XY: 74320

African (AFR) AF: 0.186 AC: 7737 AN: 41490

American (AMR) AF: 0.305 AC: 4664 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1144 AN: 3472

East Asian (EAS) AF: 0.476 AC: 2455 AN: 5158

South Asian (SAS) AF: 0.242 AC: 1163 AN: 4812

European-Finnish (FIN) AF: 0.330 AC: 3490 AN: 10566

Middle Eastern (MID) AF: 0.283 AC: 82 AN: 290

European-Non Finnish (NFE) AF: 0.351 AC: 23830 AN: 67970

Other (OTH) AF: 0.291 AC: 616 AN: 2116

Alfa AF: 0.332 Hom.: 5081

Bravo AF: 0.294

Asia WGS AF: 0.317 AC: 1103 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.18
DANN	Benign	0.65
PhyloP100		-0.80
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: rs1076514; hg19: chr16-78159032;