NM_024908.4:c.652A>G

Variant names:

• chr15-43839648-A-G
• rs970854697
• NM_024908.4:c.652A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024908.4(WDR76):​c.652A>G​(p.Met218Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024908.4. 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
	WDR76	NM_024908.4	MANE Select	c.652A>G	p.Met218Val	missense	Exon 5 of 13	NP_079184.2	Q9H967
	WDR76	NM_001167941.2		c.460A>G	p.Met154Val	missense	Exon 5 of 13	NP_001161413.1	A0A0C4DFX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR76	ENST00000263795.11	TSL:1 MANE Select	c.652A>G	p.Met218Val	missense	Exon 5 of 13	ENSP00000263795.6	Q9H967
	WDR76	ENST00000381246.6	TSL:1	c.460A>G	p.Met154Val	missense	Exon 5 of 13	ENSP00000370645.2	A0A0C4DFX7
	WDR76	ENST00000965236.1		c.562A>G	p.Met188Val	missense	Exon 4 of 12	ENSP00000635295.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460746 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726672

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000448 AC: 2 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111296

Other (OTH) AF: 0.0000663 AC: 4 AN: 60330

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.056	T
Polyphen		0.93	P
Vest4		0.71
MutPred		0.35		Loss of sheet (P = 0.0037)
MVP		0.69
MPC		0.33
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.37
gMVP		0.47
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs970854697; hg19: chr15-44131846;