NM_001366157.1:c.2825G>A

Variant names:

• chr3-167505366-C-T
• rs761602862
• NM_001366157.1:c.2825G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001366157.1(WDR49):​c.2825G>A​(p.Ser942Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,529,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S942R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.188

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04339689).
• BP6: Variant 3-167505366-C-T is Benign according to our data. Variant chr3-167505366-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3816019.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR49	NM_001366157.1	c.2825G>A	p.Ser942Asn	missense_variant	Exon 17 of 19	ENST00000682715.1	NP_001353086.1
WDR49	NM_001348951.2	c.2792G>A	p.Ser931Asn	missense_variant	Exon 17 of 19		NP_001335880.1
WDR49	NM_001348952.2	c.2792G>A	p.Ser931Asn	missense_variant	Exon 17 of 19		NP_001335881.1
WDR49	NM_001366158.1	c.1769G>A	p.Ser590Asn	missense_variant	Exon 14 of 16		NP_001353087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR49	ENST00000682715.1	c.2825G>A	p.Ser942Asn	missense_variant	Exon 17 of 19		NM_001366157.1	ENSP00000507497.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000206 AC: 4 AN: 194294 Hom.: 0 AF XY: 0.00000935 AC XY: 1 AN XY: 106958

Gnomad AFR exome AF: 0.0000746

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000502

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 19 AN: 1377660 Hom.: 0 Cov.: 31 AF XY: 0.0000117 AC XY: 8 AN XY: 683038

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: 0.0000140

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74266

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 08, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.052
DANN	Benign	0.16
DEOGEN2	Benign	0.00019	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.22	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.97	N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.30	N;.;.
REVEL	Benign	0.032
Sift	Benign	0.75	T;.;.
Sift4G	Benign	1.0	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.12
MVP		0.28
MPC		0.028
ClinPred		0.030	T
GERP RS		-3.0
Varity_R		0.038
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs761602862; hg19: chr3-167223154;