NM_024908.4:c.704C>G

Variant names:

• chr15-43839700-C-G
• rs758056977
• NM_024908.4:c.704C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024908.4(WDR76):​c.704C>G​(p.Thr235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T235I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07439822).

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.704C>G	p.Thr235Arg	missense	Exon 5 of 13	NP_079184.2	Q9H967
	WDR76	NM_001167941.2		c.512C>G	p.Thr171Arg	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.704C>G	p.Thr235Arg	missense	Exon 5 of 13	ENSP00000263795.6	Q9H967
	WDR76	ENST00000381246.6	TSL:1	c.512C>G	p.Thr171Arg	missense	Exon 5 of 13	ENSP00000370645.2	A0A0C4DFX7
	WDR76	ENST00000965236.1		c.614C>G	p.Thr205Arg	missense	Exon 4 of 12	ENSP00000635295.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458200 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725410

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

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109856

Other (OTH) AF: 0.00 AC: 0 AN: 60180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.4
DANN	Benign	0.68
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.013
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Benign	0.079	T
Polyphen		0.0010	B
Vest4		0.26
MutPred		0.34		Gain of sheet (P = 0.0028)
MVP		0.26
MPC		0.15
ClinPred		0.042	T
GERP RS		-2.2
Varity_R		0.036
gMVP		0.28
Mutation Taster		=92/8	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: rs758056977; hg19: chr15-44131898;