NM_001029896.2:c.1021G>A

Variant names:

• chrX-49074865-C-T
• rs1557083823
• NM_001029896.2:c.1021G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001029896.2(WDR45):​c.1021G>A​(p.Gly341Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1021G>A	p.Gly341Arg	missense	Exon 11 of 11	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.1024G>A	p.Gly342Arg	missense	Exon 12 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.1021G>A	p.Gly341Arg	missense	Exon 11 of 11	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.1024G>A	p.Gly342Arg	missense	Exon 12 of 12	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.1024G>A	p.Gly342Arg	missense	Exon 11 of 11	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodegeneration with brain iron accumulation 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.64		Loss of sheet (P = 0.007)
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.92
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557083823; hg19: chrX-48932524;