16-78115069-C-G

Variant names:

• chr16-78115069-C-G
• rs377442022
• NM_016373.4:c.324C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016373.4(WWOX):​c.324C>G​(p.Asp108Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D108N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_130791.5	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 6		NP_570607.1
WWOX	NM_001291997.2	c.-16C>G		5_prime_UTR_variant	Exon 3 of 8		NP_001278926.1
WWOX	NR_120436.3	n.563C>G		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.324C>G	p.Asp108Glu	missense_variant	Exon 4 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249576 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135408

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	9.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D;T;D;D
Sift4G	Uncertain	0.015	D;D;D;D;T;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.79
MutPred		0.23		Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);Gain of glycosylation at S110 (P = 0.0909);
MVP		0.78
ClinPred		0.98	D
GERP RS		-3.9
Varity_R		0.41
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs377442022; hg19: chr16-78148966;