15-43839681-T-A

Position:

• chr15-43839681-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024908.4(WDR76):​c.685T>A​(p.Ser229Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.135

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08118433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR76	NM_024908.4	c.685T>A	p.Ser229Thr	missense_variant	5/13	ENST00000263795.11	NP_079184.2
WDR76	NM_001167941.2	c.493T>A	p.Ser165Thr	missense_variant	5/13		NP_001161413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR76	ENST00000263795.11	c.685T>A	p.Ser229Thr	missense_variant	5/13	1	NM_024908.4	ENSP00000263795.6
WDR76	ENST00000381246.6	c.493T>A	p.Ser165Thr	missense_variant	5/13	1		ENSP00000370645.2
WDR76	ENST00000452115.1	c.493T>A	p.Ser165Thr	missense_variant	5/7	5		ENSP00000404665.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460012 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726308

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 06, 2021

The c.685T>A (p.S229T) alteration is located in exon 5 (coding exon 5) of the WDR76 gene. This alteration results from a T to A substitution at nucleotide position 685, causing the serine (S) at amino acid position 229 to be replaced by a threonine (T). 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	0.075
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.096
DEOGEN2	Benign	0.015	T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.99	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.14
MutPred		0.28		Gain of sheet (P = 0.0221);.;.;
MVP		0.53
MPC		0.12
ClinPred		0.032	T
GERP RS		-2.2
Varity_R		0.034
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1282788555; hg19: chr15-44131879;