15-43842439-G-A

Position:

• chr15-43842439-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024908.4(WDR76):​c.757G>A​(p.Glu253Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

WDR76 (HGNC:25773): (WD repeat domain 76) Enables enzyme binding activity. Involved in cellular response to DNA damage stimulus. Located in heterochromatin; nucleus; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37169963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR76	NM_024908.4	c.757G>A	p.Glu253Lys	missense_variant	6/13	ENST00000263795.11	NP_079184.2
WDR76	NM_001167941.2	c.565G>A	p.Glu189Lys	missense_variant	6/13		NP_001161413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR76	ENST00000263795.11	c.757G>A	p.Glu253Lys	missense_variant	6/13	1	NM_024908.4	ENSP00000263795.6
WDR76	ENST00000381246.6	c.565G>A	p.Glu189Lys	missense_variant	6/13	1		ENSP00000370645.2
WDR76	ENST00000452115.1	c.565G>A	p.Glu189Lys	missense_variant	6/7	5		ENSP00000404665.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.757G>A (p.E253K) alteration is located in exon 6 (coding exon 6) of the WDR76 gene. This alteration results from a G to A substitution at nucleotide position 757, causing the glutamic acid (E) at amino acid position 253 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.019	T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.14	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.51
MutPred		0.31		Gain of ubiquitination at E253 (P = 0.0031);.;.;
MVP		0.87
MPC		0.24
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.16
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs996958442; hg19: chr15-44134637;