rs7192129

Variant names:

• chr16-78102517-C-T
• rs7192129
• NM_016373.4:c.107+2632C>T

Variant summary

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

The NM_016373.4(WWOX):​c.107+2632C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 152,100 control chromosomes in the GnomAD database, including 30,659 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 0.63 (30659 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.107+2632C>T		intron_variant	Intron 1 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.-168+2632C>T		intron_variant	Intron 1 of 7		NP_001278926.1
WWOX	NM_130791.5	c.107+2632C>T		intron_variant	Intron 1 of 5		NP_570607.1
WWOX	NR_120436.3	n.346+2518C>T		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.107+2632C>T		intron_variant	Intron 1 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95304 AN: 151982 Hom.: 30646 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.651

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

GnomAD4 genome AF: 0.627 AC: 95355 AN: 152100 Hom.: 30659 Cov.: 33 AF XY: 0.630 AC XY: 46813 AN XY: 74342

African (AFR) AF: 0.477 AC: 19778 AN: 41456

American (AMR) AF: 0.674 AC: 10301 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2307 AN: 3466

East Asian (EAS) AF: 0.592 AC: 3054 AN: 5160

South Asian (SAS) AF: 0.749 AC: 3609 AN: 4820

European-Finnish (FIN) AF: 0.705 AC: 7468 AN: 10592

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46556 AN: 67990

Other (OTH) AF: 0.651 AC: 1377 AN: 2116

Alfa AF: 0.665 Hom.: 44605

Bravo AF: 0.614

Asia WGS AF: 0.679 AC: 2358 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.46
PhyloP100		0.20
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: rs7192129; hg19: chr16-78136414;