3-167505396-A-G

Variant summary

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

The NM_001366157.1(WDR49):c.2795T>C(p.Ile932Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,522,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: WDR49 NM_001366157.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.285

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059674203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR49	NM_001366157.1	c.2795T>C	p.Ile932Thr	missense_variant	17/19	ENST00000682715.1
WDR49	NM_001348951.2	c.2762T>C	p.Ile921Thr	missense_variant	17/19
WDR49	NM_001348952.2	c.2762T>C	p.Ile921Thr	missense_variant	17/19
WDR49	NM_001366158.1	c.1739T>C	p.Ile580Thr	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR49	ENST00000682715.1	c.2795T>C	p.Ile932Thr	missense_variant	17/19		NM_001366157.1	A2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000418 AC: 78 AN: 186680 Hom.: 0 AF XY: 0.000436 AC XY: 45 AN XY: 103304

Gnomad AFR exome AF: 0.0000811

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000414

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.000743

GnomAD4 exome AF: 0.000428 AC: 586 AN: 1369752 Hom.: 0 Cov.: 31 AF XY: 0.000408 AC XY: 277 AN XY: 679132

Gnomad4 AFR exome AF: 0.0000700

Gnomad4 AMR exome AF: 0.000152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000287

Gnomad4 FIN exome AF: 0.000509

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.000445

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74460

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000705 AC: 6

ExAC AF: 0.000446 AC: 54

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

Dec 14, 2023

The c.1739T>C (p.I580T) alteration is located in exon 13 (coding exon 12) of the WDR49 gene. This alteration results from a T to C substitution at nucleotide position 1739, causing the isoleucine (I) at amino acid position 580 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.9
Dann	Benign	0.96
DEOGEN2	Benign	0.00021	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.93	N;.;.
REVEL	Benign	0.063
Sift	Benign	0.62	T;.;.
Sift4G	Benign	0.55	T;.;.
Polyphen		0.0030	B;.;.
Vest4		0.22
MVP		0.51
MPC		0.033
ClinPred		1.0	D
GERP RS		0.73
Varity_R		0.024
gMVP		0.038

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

Publications

LitVar

Other links and lift over

dbSNP: rs143304878; hg19: chr3-167223184;