rs140060332

Variant names:

• chr16-79211799-G-T
• rs140060332
• ENST00000402655.6:c.601G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The ENST00000402655.6(WWOX):​c.601G>T​(p.Gly201*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,018 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (64 hom.)
• Consequence: WWOX ENST00000402655.6 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.70
• Publications: 3 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]

ENSG00000261722 (HGNC:):

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), Ambry Genetics, G2P
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.358 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 16-79211799-G-T is Benign according to our data. Variant chr16-79211799-G-T is described in ClinVar as Benign. ClinVar VariationId is 382759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.003 (457/152332) while in subpopulation AMR AF = 0.0233 (356/15306). AF 95% confidence interval is 0.0213. There are 4 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000402655.6. 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.*3G>T		3_prime_UTR	Exon 9 of 9	NP_057457.1
	WWOX	NM_001291997.2		c.*3G>T		3_prime_UTR	Exon 8 of 8	NP_001278926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000402655.6	TSL:1	c.601G>T	p.Gly201*	stop_gained	Exon 5 of 5	ENSP00000384238.2
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.*3G>T		3_prime_UTR	Exon 9 of 9	ENSP00000457230.1
	WWOX	ENST00000406884.6	TSL:1	c.*3G>T		3_prime_UTR	Exon 6 of 6	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00762 AC: 1893 AN: 248328 AF XY: 0.00570

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.0468

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00202 AC: 2948 AN: 1461686 Hom.: 64 Cov.: 89 AF XY: 0.00172 AC XY: 1252 AN XY: 727160

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.0457 AC: 2042 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0184 AC: 729 AN: 39698

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111928

Other (OTH) AF: 0.00190 AC: 115 AN: 60388

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74490

African (AFR) AF: 0.000649 AC: 27 AN: 41590

American (AMR) AF: 0.0233 AC: 356 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0126 AC: 65 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00496

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00553 AC: 669

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.97
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.75	D
PhyloP100		1.7
Vest4		0.24
ClinPred		0.011	T
GERP RS		0.044
Mutation Taster		=175/25	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: rs140060332; hg19: chr16-79245696;