3-167522363-G-A

Variant names:

• chr3-167522363-G-A
• rs199917200
• NM_001366157.1:c.2726C>T

Variant summary

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

The NM_001366157.1(WDR49):​c.2726C>T​(p.Thr909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 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. T909R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2726C>T	p.Thr909Ile	missense	Exon 16 of 19	NP_001353086.1
	WDR49	NM_001348951.2		c.2693C>T	p.Thr898Ile	missense	Exon 16 of 19	NP_001335880.1	A0A3B3IS43
	WDR49	NM_001348952.2		c.2693C>T	p.Thr898Ile	missense	Exon 16 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.2726C>T	p.Thr909Ile	missense	Exon 16 of 19	ENSP00000507497.1	Q8IV35-1
	WDR49	ENST00000308378.7	TSL:1	c.1670C>T	p.Thr557Ile	missense	Exon 12 of 15	ENSP00000311343.3	Q8IV35-3
	WDR49	ENST00000647816.2		c.2693C>T	p.Thr898Ile	missense	Exon 16 of 19	ENSP00000497120.1	A0A3B3IS43

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722584

⚠️ 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: 32842

American (AMR) AF: 0.0000236 AC: 1 AN: 42316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 84044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109856

Other (OTH) AF: 0.00 AC: 0 AN: 59998

⚠️ 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	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.4
DANN	Benign	0.97
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.30
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.015
Sift	Benign	0.24	T
Sift4G	Benign	0.24	T
Polyphen		0.080	B
Vest4		0.11
MutPred		0.16		Gain of glycosylation at S552 (P = 0.0139)
MVP		0.18
MPC		0.030
ClinPred		0.12	T
GERP RS		1.0
Varity_R		0.049
gMVP		0.047
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: -48

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

Other links and lift over

dbSNP: rs199917200; hg19: chr3-167240151;