X-49075271-C-T

Position:

• chrX-49075271-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001029896.2(WDR45):​c.838G>A​(p.Val280Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,209,412 control chromosomes in the GnomAD database, including 51 homozygotes. There are 829 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (18 hom., 288 hem., cov: 24)
  • Exomes 𝑓: 0.0018 (33 hom. 541 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.26

Genes affected

WDR45 (HGNC:28912): (WD repeat domain 45) This gene encodes a member of the WD repeat protein family. 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. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

ENSG00000288053 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005992919).
• BP6: Variant X-49075271-C-T is Benign according to our data. Variant chrX-49075271-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49075271-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.838G>A	p.Val280Met	missense_variant	10/11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.841G>A	p.Val281Met	missense_variant	11/12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.838G>A	p.Val280Met	missense_variant	10/11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.521+93G>A		intron_variant		2		ENSP00000365536.3

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 755 AN: 112294 Hom.: 18 Cov.: 24 AF XY: 0.00829 AC XY: 286 AN XY: 34496

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00364

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000245

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00670 AC: 1209 AN: 180428 Hom.: 19 AF XY: 0.00491 AC XY: 322 AN XY: 65530

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.0394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00414

Gnomad SAS exome AF: 0.000531

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00178 AC: 1957 AN: 1097065 Hom.: 33 Cov.: 32 AF XY: 0.00149 AC XY: 541 AN XY: 362495

Gnomad4 AFR exome AF: 0.000872

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00282

Gnomad4 SAS exome AF: 0.000500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000915

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.00675 AC: 758 AN: 112347 Hom.: 18 Cov.: 24 AF XY: 0.00833 AC XY: 288 AN XY: 34559

Gnomad4 AFR AF: 0.00129

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00365

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000245

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.000877 Hom.: 26

Bravo AF: 0.0108

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00349 AC: 424

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 17, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neurodegeneration with brain iron accumulation 5;C3808786:Oculocutaneous albinism type 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 30, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

This alteration is classified as 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. -

Neurodegeneration with brain iron accumulation 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.041	T;T;T;.;T;.;.;.;.;T;.;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;.;D;D;D;D;D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.070	N;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.50	N;.;.;.;.;N;N;N;N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.61	T;.;.;.;.;T;T;T;T;.;.;.
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.027	B;B;.;.;.;B;B;B;B;.;.;.
Vest4		0.28
MVP		0.60
MPC		0.62
ClinPred		0.021	T
GERP RS		4.1
Varity_R		0.27
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149509552; hg19: chrX-48932930; COSMIC: COSV59875896; COSMIC: COSV59875896;