16-78099740-A-T

Variant names:

• chr16-78099740-A-T
• rs377066400
• NM_016373.4:c.-39A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_016373.4(WWOX):​c.-39A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,517,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: WWOX NM_016373.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.849
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-78099740-A-T is Benign according to our data. Variant chr16-78099740-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 514318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000388 (59/152236) while in subpopulation AFR AF = 0.00128 (53/41468). AF 95% confidence interval is 0.001. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.-39A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_016373.4	c.-39A>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000566780.6	NP_057457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.-39A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1
WWOX	ENST00000566780.6	c.-39A>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000117 AC: 14 AN: 120100 AF XY: 0.0000923

Gnomad AFR exome AF: 0.00238

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000306

GnomAD4 exome AF: 0.0000410 AC: 56 AN: 1364820 Hom.: 1 Cov.: 29 AF XY: 0.0000372 AC XY: 25 AN XY: 671904

African (AFR) AF: 0.00157 AC: 46 AN: 29294

American (AMR) AF: 0.0000675 AC: 2 AN: 29642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23490

East Asian (EAS) AF: 0.00 AC: 0 AN: 33790

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47848

Middle Eastern (MID) AF: 0.000239 AC: 1 AN: 4186

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1064910

Other (OTH) AF: 0.000106 AC: 6 AN: 56390

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74380

African (AFR) AF: 0.00128 AC: 53 AN: 41468

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 29, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.6
DANN	Benign	0.58
PhyloP100		-0.85
PromoterAI		-0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs377066400; hg19: chr16-78133637;