rs117065412

Variant names:

• chr16-79211789-C-A
• rs117065412
• NM_016373.4:c.1238C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-79211789-C-A
• chr16-79211789-C-G
• chr16-79211789-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016373.4(WWOX):​c.1238C>A​(p.Ser413Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,074 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S413C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (17 hom., cov: 33)
  • Exomes 𝑓: 0.019 (289 hom.)
• Consequence: WWOX NM_016373.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.66
• Publications: 10 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]

MAF (HGNC:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

MAF Gene-Disease associations (from GenCC):

• Ayme-Gripp syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract 21 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fine-Lubinsky syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261722 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003261149).
• BP6: Variant 16-79211789-C-A is Benign according to our data. Variant chr16-79211789-C-A is described in ClinVar as Benign. ClinVar VariationId is 241099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2088/152302) while in subpopulation NFE AF = 0.0215 (1462/68006). AF 95% confidence interval is 0.0206. There are 17 homozygotes in GnomAd4. There are 977 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1238C>A	p.Ser413Tyr	missense	Exon 9 of 9	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.899C>A	p.Ser300Tyr	missense	Exon 8 of 8	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1238C>A	p.Ser413Tyr	missense	Exon 9 of 9	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000406884.6	TSL:1	c.698C>A	p.Ser233Tyr	missense	Exon 6 of 6	ENSP00000384495.2	Q9NZC7-5
	WWOX	ENST00000402655.6	TSL:1	c.591C>A	p.Val197Val	synonymous	Exon 5 of 5	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2087 AN: 152184 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0128 AC: 3186 AN: 248544 AF XY: 0.0132

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.00696

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0187 AC: 27391 AN: 1461772 Hom.: 289 Cov.: 89 AF XY: 0.0185 AC XY: 13443 AN XY: 727192

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.00742 AC: 332 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 537 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00632 AC: 545 AN: 86248

European-Finnish (FIN) AF: 0.00781 AC: 417 AN: 53384

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0219 AC: 24351 AN: 1111954

Other (OTH) AF: 0.0175 AC: 1054 AN: 60384

GnomAD4 genome AF: 0.0137 AC: 2088 AN: 152302 Hom.: 17 Cov.: 33 AF XY: 0.0131 AC XY: 977 AN XY: 74474

African (AFR) AF: 0.00349 AC: 145 AN: 41582

American (AMR) AF: 0.0150 AC: 230 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1462 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0178 Hom.: 105

Bravo AF: 0.0134

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00255 AC: 10

ESP6500EA AF: 0.0218 AC: 181

ExAC AF: 0.0127 AC: 1535

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0204

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (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
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.060
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.79	T
PhyloP100		4.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		0.070	B
Vest4		0.32
ClinPred		0.020	T
GERP RS		5.7
Varity_R		0.24
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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: rs117065412; hg19: chr16-79245686; COSMIC: COSV68371157; COSMIC: COSV68371157;