16-79212426-G-A

Variant names:

• chr16-79212426-G-A
• rs12828
• NM_016373.4:c.*630G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016373.4(WWOX):​c.*630G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 314,970 control chromosomes in the GnomAD database, including 46,273 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20925 hom., cov: 33)
  • Exomes 𝑓: 0.54 (25348 hom.)
• Consequence: WWOX NM_016373.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 17 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.*630G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000566780.6	NP_057457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.*630G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76733 AN: 151880 Hom.: 20915 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.510

GnomAD4 exome AF: 0.543 AC: 88516 AN: 162974 Hom.: 25348 Cov.: 3 AF XY: 0.542 AC XY: 44594 AN XY: 82272

African (AFR) AF: 0.325 AC: 2143 AN: 6588

American (AMR) AF: 0.413 AC: 3009 AN: 7280

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 3189 AN: 5834

East Asian (EAS) AF: 0.352 AC: 4872 AN: 13856

South Asian (SAS) AF: 0.344 AC: 2475 AN: 7198

European-Finnish (FIN) AF: 0.624 AC: 5018 AN: 8038

Middle Eastern (MID) AF: 0.442 AC: 333 AN: 754

European-Non Finnish (NFE) AF: 0.602 AC: 61870 AN: 102756

Other (OTH) AF: 0.525 AC: 5607 AN: 10670

GnomAD4 genome AF: 0.505 AC: 76764 AN: 151996 Hom.: 20925 Cov.: 33 AF XY: 0.500 AC XY: 37163 AN XY: 74318

African (AFR) AF: 0.334 AC: 13834 AN: 41408

American (AMR) AF: 0.425 AC: 6501 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3468

East Asian (EAS) AF: 0.339 AC: 1747 AN: 5156

South Asian (SAS) AF: 0.354 AC: 1706 AN: 4824

European-Finnish (FIN) AF: 0.654 AC: 6919 AN: 10584

Middle Eastern (MID) AF: 0.448 AC: 130 AN: 290

European-Non Finnish (NFE) AF: 0.623 AC: 42361 AN: 67960

Other (OTH) AF: 0.502 AC: 1060 AN: 2112

Alfa AF: 0.556 Hom.: 13581

Bravo AF: 0.486

Asia WGS AF: 0.329 AC: 1144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.078
DANN	Benign	0.46
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs12828; hg19: chr16-79246323;