4-10075437-G-T

Variant summary

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

The NM_017491.5(WDR1):c.1762C>A(p.His588Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR1 NM_017491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06

Genes affected

WDR1 (HGNC:12754): (WD repeat domain 1) This gene encodes a protein containing 9 WD repeats. WD repeats are approximately 30- to 40-amino acid domains containing several conserved residues, mostly including a trp-asp at the C-terminal end. WD domains are involved in protein-protein interactions. The encoded protein may help induce the disassembly of actin filaments. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.05067721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR1	NM_017491.5	c.1762C>A	p.His588Asn	missense_variant	15/15	ENST00000499869.7
WDR1	NM_005112.5	c.1342C>A	p.His448Asn	missense_variant	12/12
WDR1	XM_017008880.3	c.1921C>A	p.His641Asn	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR1	ENST00000499869.7	c.1762C>A	p.His588Asn	missense_variant	15/15	5	NM_017491.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with WDR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 588 of the WDR1 protein (p.His588Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Benign	0.87
DEOGEN2	Benign	0.083	T;.;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.051	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.91	N;N;N;N
REVEL	Benign	0.072
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.97	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.21
MutPred		0.27		Loss of glycosylation at T592 (P = 0.0398);.;Loss of glycosylation at T592 (P = 0.0398);.;
MVP		0.068
MPC		0.46
ClinPred		0.40	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-10077061;