rs66481974

Variant names:

• chr16-79211594-T-C
• rs66481974
• NM_016373.4:c.1057-14T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-79211594-T-C
• chr16-79211594-T-A
• chr16-79211594-T-G

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.1057-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,614,050 control chromosomes in the GnomAD database, including 1,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (120 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1565 hom.)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.909
• 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]

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 (BayesDel_noAF=-0.8).
• BP6: Variant 16-79211594-T-C is Benign according to our data. Variant chr16-79211594-T-C is described in ClinVar as Benign. ClinVar VariationId is 260736.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 = 0.0372 (5658/152262) while in subpopulation NFE AF = 0.0474 (3226/68028). AF 95% confidence interval is 0.0461. There are 120 homozygotes in GnomAd4. There are 2802 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 120 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.1057-14T>C		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.718-14T>C		intron	N/A	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-14T>C		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000402655.6	TSL:1	c.410-14T>C		intron	N/A	ENSP00000384238.2	Q9NZC7-6
	WWOX	ENST00000406884.6	TSL:1	c.517-14T>C		intron	N/A	ENSP00000384495.2	Q9NZC7-5

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5656 AN: 152144 Hom.: 120 Cov.: 33

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0373 AC: 9248 AN: 248250 AF XY: 0.0382

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0333

Gnomad EAS exome AF: 0.0237

Gnomad FIN exome AF: 0.0621

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0440 AC: 64297 AN: 1461788 Hom.: 1565 Cov.: 84 AF XY: 0.0442 AC XY: 32151 AN XY: 727206

African (AFR) AF: 0.0198 AC: 662 AN: 33466

American (AMR) AF: 0.0156 AC: 697 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0327 AC: 855 AN: 26134

East Asian (EAS) AF: 0.0346 AC: 1375 AN: 39692

South Asian (SAS) AF: 0.0349 AC: 3008 AN: 86246

European-Finnish (FIN) AF: 0.0612 AC: 3268 AN: 53418

Middle Eastern (MID) AF: 0.0227 AC: 131 AN: 5768

European-Non Finnish (NFE) AF: 0.0465 AC: 51756 AN: 1111970

Other (OTH) AF: 0.0421 AC: 2545 AN: 60388

GnomAD4 genome AF: 0.0372 AC: 5658 AN: 152262 Hom.: 120 Cov.: 33 AF XY: 0.0376 AC XY: 2802 AN XY: 74434

African (AFR) AF: 0.0218 AC: 907 AN: 41562

American (AMR) AF: 0.0232 AC: 355 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3466

East Asian (EAS) AF: 0.0263 AC: 136 AN: 5174

South Asian (SAS) AF: 0.0351 AC: 169 AN: 4818

European-Finnish (FIN) AF: 0.0641 AC: 679 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0474 AC: 3226 AN: 68028

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0334 Hom.: 27

Bravo AF: 0.0328

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

ClinVar submissions

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	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	Developmental and epileptic encephalopathy, 28 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.1
DANN	Benign	0.73
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs66481974; hg19: chr16-79245491;