15-43828121-A-G

Position:

• chr15-43828121-A-G

Variant summary

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

The NM_024908.4(WDR76):​c.217A>G​(p.Lys73Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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=0.11370751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR76	NM_024908.4	c.217A>G	p.Lys73Glu	missense_variant	2/13	ENST00000263795.11	NP_079184.2
WDR76	NM_001167941.2	c.25A>G	p.Lys9Glu	missense_variant	2/13		NP_001161413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR76	ENST00000263795.11	c.217A>G	p.Lys73Glu	missense_variant	2/13	1	NM_024908.4	ENSP00000263795.6
WDR76	ENST00000381246.6	c.25A>G	p.Lys9Glu	missense_variant	2/13	1		ENSP00000370645.2
WDR76	ENST00000452115.1	c.25A>G	p.Lys9Glu	missense_variant	2/7	5		ENSP00000404665.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Mar 18, 2024

The c.217A>G (p.K73E) alteration is located in exon 2 (coding exon 2) of the WDR76 gene. This alteration results from a A to G substitution at nucleotide position 217, causing the lysine (K) at amino acid position 73 to be replaced by a glutamic acid (E). 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	0.071
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0056	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.051	T;D;D
Sift4G	Benign	0.084	T;T;T
Polyphen		0.61	P;.;.
Vest4		0.15
MutPred		0.26		Loss of ubiquitination at K73 (P = 0.0022);.;.;
MVP		0.59
MPC		0.19
ClinPred		0.12	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-44120319;