rs140596058

chrX-49076515-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001029896.2(WDR45):c.351C>T(p.Ile117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,210,619 control chromosomes in the GnomAD database, including 3 homozygotes. There are 720 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 32 hem., cov: 24)
  • Exomes 𝑓: 0.0022 (3 hom. 688 hem.)
• Consequence: WDR45 NM_001029896.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.414

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-49076515-G-A is Benign according to our data. Variant chrX-49076515-G-A is described in ClinVar as [Benign]. Clinvar id is 383408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49076515-G-A is described in Lovd as [Likely_benign]. Variant chrX-49076515-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.414 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00102 (115/112577) while in subpopulation NFE AF= 0.00178 (95/53262). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.351C>T	p.Ile117=	synonymous_variant	6/11	ENST00000376372.9
WDR45	NM_007075.4	c.354C>T	p.Ile118=	synonymous_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.351C>T	p.Ile117=	synonymous_variant	6/11	1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 115 AN: 112524 Hom.: 0 Cov.: 24 AF XY: 0.000923 AC XY: 32 AN XY: 34672

Gnomad AFR AF: 0.000451

Gnomad AMI AF: 0.00147

Gnomad AMR AF: 0.000188

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: 0.00178

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000895 AC: 164 AN: 183314 Hom.: 0 AF XY: 0.000812 AC XY: 55 AN XY: 67768

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.00216 AC: 2371 AN: 1098042 Hom.: 3 Cov.: 31 AF XY: 0.00189 AC XY: 688 AN XY: 363422

Gnomad4 AFR exome AF: 0.000417

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000197

Gnomad4 NFE exome AF: 0.00269

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00102 AC: 115 AN: 112577 Hom.: 0 Cov.: 24 AF XY: 0.000921 AC XY: 32 AN XY: 34735

Gnomad4 AFR AF: 0.000450

Gnomad4 AMR AF: 0.000187

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.00148 Hom.: 8

Bravo AF: 0.000880

EpiCase AF: 0.00174

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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. -

Neurodegeneration with brain iron accumulation 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.6
Dann	Benign	0.89

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: rs140596058; hg19: chrX-48934174;