X-49074865-C-G

Variant names:

• chrX-49074865-C-G
• rs1557083823
• NM_001029896.2:c.1021G>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.1021G>C​(p.Gly341Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,947 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

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

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183497 AF XY: 0.0000147

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097947 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363313

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4089

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841916

Other (OTH) AF: 0.00 AC: 0 AN: 46078

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

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	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	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		0.99	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)		0.040		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: rs1557083823; hg19: chrX-48932524;