rs782302447

Variant names:

• chrX-49076514-C-T
• rs782302447
• NM_001029896.2:c.352G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001029896.2(WDR45):​c.352G>A​(p.Val118Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,098,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000014 (0 hom. 6 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.71
• Publications: 0 publications found

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]

WDR45 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Illumina, Genomics England PanelApp
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288053 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 15 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029896.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	NM_001029896.2	MANE Select	c.352G>A	p.Val118Met	missense	Exon 6 of 11	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.355G>A	p.Val119Met	missense	Exon 7 of 12	NP_009006.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	ENST00000376372.9	TSL:1 MANE Select	c.352G>A	p.Val118Met	missense	Exon 6 of 11	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.355G>A	p.Val119Met	missense	Exon 7 of 12	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.355G>A	p.Val119Met	missense	Exon 6 of 11	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183333 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1098082 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 363458

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 842018

Other (OTH) AF: 0.0000434 AC: 2 AN: 46087

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Neurodegeneration with brain iron accumulation 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.38
MutPred		0.68		Gain of MoRF binding (P = 0.0968)
MVP		0.76
MPC		1.1
ClinPred		0.78	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.71
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782302447; hg19: chrX-48934173;