Genetic Variant WDR1:p.Asp572Gly (chr4-10075484-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_017491.5(WDR1):c.1715A>G(p.Asp572Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,610 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D572V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WDR1
NM_017491.5 missense, splice_region

Scores

Splicing: ADA: 0.0006496

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.56

Publications

0 publications found

Variant links:

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]

WDR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-10075484-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 974605.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18559676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR1	NM_017491.5 link	c.1715A>G	p.Asp572Gly	missense_variant, splice_region_variant	Exon 15 of 15	ENST00000499869.7	NP_059830.1	O75083-1V9HWG7
WDR1	NM_005112.5 link	c.1295A>G	p.Asp432Gly	missense_variant, splice_region_variant	Exon 12 of 12		NP_005103.2	O75083-3
WDR1	XM_017008880.3 link	c.1874A>G	p.Asp625Gly	missense_variant, splice_region_variant	Exon 15 of 15		XP_016864369.1	A0A8V8TP22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR1	ENST00000499869.7 link	c.1715A>G	p.Asp572Gly	missense_variant, splice_region_variant	Exon 15 of 15	5	NM_017491.5	ENSP00000427687.1		O75083-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111842

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.0029

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.091

T;.;T;.

Eigen

Benign

0.032

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;L;.

PhyloP100

7.6

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.20

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.49

T;T;T;T

Sift4G

Benign

0.74

T;T;T;T

Polyphen

0.038

B;D;B;D

Vest4

0.57

MutPred

0.30

Gain of MoRF binding (P = 0.0838);.;Gain of MoRF binding (P = 0.0838);.;

MVP

0.27

MPC

1.3

ClinPred

0.88

GERP RS

4.5

Varity_R

0.23

gMVP

0.73

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00065

dbscSNV1_RF

Benign

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over