rs373964828

Variant names:

• chr3-167505358-T-G
• rs373964828
• NM_001366157.1:c.2833A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-167505358-T-G
• chr3-167505358-T-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001366157.1(WDR49):​c.2833A>C​(p.Met945Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,537,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

Genes affected

WDR49 (HGNC:26587): (WD repeat domain 49) This gene encodes a member of the WD repeat protein family with nine WD repeats. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022044212).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366157.1. 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
	WDR49	NM_001366157.1	MANE Select	c.2833A>C	p.Met945Leu	missense	Exon 17 of 19	NP_001353086.1
	WDR49	NM_001348951.2		c.2800A>C	p.Met934Leu	missense	Exon 17 of 19	NP_001335880.1	A0A3B3IS43
	WDR49	NM_001348952.2		c.2800A>C	p.Met934Leu	missense	Exon 17 of 19	NP_001335881.1	A0A3B3IS43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR49	ENST00000682715.1	MANE Select	c.2833A>C	p.Met945Leu	missense	Exon 17 of 19	ENSP00000507497.1	Q8IV35-1
	WDR49	ENST00000308378.7	TSL:1	c.1777A>C	p.Met593Leu	missense	Exon 13 of 15	ENSP00000311343.3	Q8IV35-3
	WDR49	ENST00000647816.2		c.2800A>C	p.Met934Leu	missense	Exon 17 of 19	ENSP00000497120.1	A0A3B3IS43

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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

GnomAD2 exomes AF: 0.0000301 AC: 6 AN: 199446 AF XY: 0.0000183

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000505 AC: 7 AN: 1384908 Hom.: 0 Cov.: 31 AF XY: 0.00000437 AC XY: 3 AN XY: 686702

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

African (AFR) AF: 0.000170 AC: 5 AN: 29424

American (AMR) AF: 0.0000353 AC: 1 AN: 28296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23156

East Asian (EAS) AF: 0.00 AC: 0 AN: 36980

South Asian (SAS) AF: 0.00 AC: 0 AN: 72272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5076

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082504

Other (OTH) AF: 0.0000176 AC: 1 AN: 56698

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000794958), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74474

African (AFR) AF: 0.000505 AC: 21 AN: 41584

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

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	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.9
DANN	Benign	0.29
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.039
Sift	Benign	0.55	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.36		Gain of glycosylation at T591 (P = 0.0081)
MVP		0.14
MPC		0.028
ClinPred		0.0095	T
GERP RS		1.0
Varity_R		0.089
gMVP		0.17
Mutation Taster		=94/6	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: rs373964828; hg19: chr3-167223146;