chr16-78164295-T-C

Variant names:

• chr16-78164295-T-C
• rs2303191
• NM_016373.4:c.516+6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.516+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 1,612,444 control chromosomes in the GnomAD database, including 433,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43510 hom., cov: 31)
  • Exomes 𝑓: 0.73 (390295 hom.)
• Consequence: WWOX NM_016373.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002358
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.92
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-78164295-T-C is Benign according to our data. Variant chr16-78164295-T-C is described in ClinVar as Benign. ClinVar VariationId is 260739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.516+6T>C		splice_region intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.177+6T>C		splice_region intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.516+6T>C		splice_region intron	N/A	NP_570607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.516+6T>C		splice_region intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.516+6T>C		splice_region intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.409+49141T>C		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114579 AN: 151990 Hom.: 43457 Cov.: 31

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.722

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.748 AC: 185664 AN: 248274 AF XY: 0.741

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.890

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.723

GnomAD4 exome AF: 0.730 AC: 1065815 AN: 1460336 Hom.: 390295 Cov.: 36 AF XY: 0.728 AC XY: 528886 AN XY: 726428

African (AFR) AF: 0.803 AC: 26870 AN: 33460

American (AMR) AF: 0.822 AC: 36716 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17734 AN: 26112

East Asian (EAS) AF: 0.906 AC: 35954 AN: 39684

South Asian (SAS) AF: 0.724 AC: 62354 AN: 86068

European-Finnish (FIN) AF: 0.694 AC: 37003 AN: 53356

Middle Eastern (MID) AF: 0.633 AC: 3645 AN: 5762

European-Non Finnish (NFE) AF: 0.721 AC: 801489 AN: 1110900

Other (OTH) AF: 0.730 AC: 44050 AN: 60342

GnomAD4 genome AF: 0.754 AC: 114691 AN: 152108 Hom.: 43510 Cov.: 31 AF XY: 0.753 AC XY: 55990 AN XY: 74348

African (AFR) AF: 0.799 AC: 33141 AN: 41492

American (AMR) AF: 0.792 AC: 12087 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2350 AN: 3472

East Asian (EAS) AF: 0.905 AC: 4673 AN: 5164

South Asian (SAS) AF: 0.745 AC: 3590 AN: 4820

European-Finnish (FIN) AF: 0.703 AC: 7437 AN: 10582

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.722 AC: 49085 AN: 67996

Other (OTH) AF: 0.744 AC: 1571 AN: 2112

Alfa AF: 0.731 Hom.: 17803

Bravo AF: 0.764

Asia WGS AF: 0.838 AC: 2915 AN: 3478

EpiCase AF: 0.713

EpiControl AF: 0.720

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive spinocerebellar ataxia 12 (1)
-	-	1	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	Developmental and epileptic encephalopathy, 28 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.48
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.046
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: rs2303191; hg19: chr16-78198192;