rs1557084469

Variant names:

• chrX-49077702-C-G
• rs1557084469
• NM_001029896.2:c.176G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-49077702-C-G
• chrX-49077702-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001029896.2(WDR45):​c.176G>C​(p.Arg59Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21
• 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001029896.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

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.176G>C	p.Arg59Pro	missense	Exon 4 of 11	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.176G>C	p.Arg59Pro	missense	Exon 5 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.176G>C	p.Arg59Pro	missense	Exon 4 of 11	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.176G>C	p.Arg59Pro	missense	Exon 5 of 12	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.176G>C	p.Arg59Pro	missense	Exon 4 of 11	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.51		Gain of sheet (P = 0.0477)
MVP		0.73
MPC		1.9
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.011	Neutral
Varity_R		0.94
gMVP		0.85
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1557084469; hg19: chrX-48935361;