15-43828361-T-G

Variant names:

• chr15-43828361-T-G
• rs678084
• NM_024908.4:c.457T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024908.4(WDR76):​c.457T>G​(p.Ser153Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 1,603,110 control chromosomes in the GnomAD database, including 545,139 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50396 hom., cov: 32)
  • Exomes 𝑓: 0.82 (494743 hom.)
• Consequence: WDR76 NM_024908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 39 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5750487E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR76	NM_024908.4	c.457T>G	p.Ser153Ala	missense_variant	Exon 2 of 13	ENST00000263795.11	NP_079184.2
WDR76	NM_001167941.2	c.265T>G	p.Ser89Ala	missense_variant	Exon 2 of 13		NP_001161413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR76	ENST00000263795.11	c.457T>G	p.Ser153Ala	missense_variant	Exon 2 of 13	1	NM_024908.4	ENSP00000263795.6
WDR76	ENST00000381246.6	c.265T>G	p.Ser89Ala	missense_variant	Exon 2 of 13	1		ENSP00000370645.2
WDR76	ENST00000452115.1	c.265T>G	p.Ser89Ala	missense_variant	Exon 2 of 7	5		ENSP00000404665.1

Frequencies

GnomAD3 genomes AF: 0.811 AC: 123318 AN: 152042 Hom.: 50349 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.812

GnomAD2 exomes AF: 0.839 AC: 202840 AN: 241754 AF XY: 0.834

Gnomad AFR exome AF: 0.736

Gnomad AMR exome AF: 0.897

Gnomad ASJ exome AF: 0.808

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.828

GnomAD4 exome AF: 0.824 AC: 1196179 AN: 1450950 Hom.: 494743 Cov.: 47 AF XY: 0.822 AC XY: 592543 AN XY: 720504

African (AFR) AF: 0.740 AC: 24480 AN: 33080

American (AMR) AF: 0.892 AC: 38336 AN: 42962

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 20802 AN: 25788

East Asian (EAS) AF: 0.999 AC: 39544 AN: 39594

South Asian (SAS) AF: 0.763 AC: 64124 AN: 84016

European-Finnish (FIN) AF: 0.886 AC: 46585 AN: 52592

Middle Eastern (MID) AF: 0.758 AC: 4323 AN: 5704

European-Non Finnish (NFE) AF: 0.820 AC: 908484 AN: 1107234

Other (OTH) AF: 0.825 AC: 49501 AN: 59980

GnomAD4 genome AF: 0.811 AC: 123422 AN: 152160 Hom.: 50396 Cov.: 32 AF XY: 0.815 AC XY: 60650 AN XY: 74398

African (AFR) AF: 0.739 AC: 30643 AN: 41474

American (AMR) AF: 0.853 AC: 13034 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2808 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5190

South Asian (SAS) AF: 0.780 AC: 3759 AN: 4822

European-Finnish (FIN) AF: 0.889 AC: 9430 AN: 10604

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.821 AC: 55815 AN: 68006

Other (OTH) AF: 0.814 AC: 1722 AN: 2116

Alfa AF: 0.817 Hom.: 164396

Bravo AF: 0.807

TwinsUK AF: 0.809 AC: 2998

ALSPAC AF: 0.826 AC: 3184

ESP6500AA AF: 0.740 AC: 3254

ESP6500EA AF: 0.818 AC: 7028

ExAC AF: 0.831 AC: 100844

Asia WGS AF: 0.897 AC: 3116 AN: 3478

EpiCase AF: 0.818

EpiControl AF: 0.815

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0071	T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.19	T;T;T
MetaRNN	Benign	6.6e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.061	T;T;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.036
MPC		0.11
ClinPred		0.0023	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.041
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs678084; hg19: chr15-44120559; COSMIC: COSV51041781; COSMIC: COSV51041781;