chrX-49076685-A-G

Variant names:

• chrX-49076685-A-G
• rs1557084314
• NM_001029896.2:c.301T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001029896.2(WDR45):​c.301T>C​(p.Phe101Leu) 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. 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: 6.84
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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.301T>C	p.Phe101Leu	missense	Exon 5 of 11	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.304T>C	p.Phe102Leu	missense	Exon 6 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.301T>C	p.Phe101Leu	missense	Exon 5 of 11	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.304T>C	p.Phe102Leu	missense	Exon 6 of 12	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.304T>C	p.Phe102Leu	missense	Exon 5 of 11	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

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	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.066	T
Polyphen		0.73	P
Vest4		0.58
MutPred		0.72		Gain of sheet (P = 0.0827)
MVP		0.57
MPC		0.93
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.79
gMVP		0.77
Mutation Taster		=52/48	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: rs1557084314; hg19: chrX-48934344;