X-49076502-G-C

Position:

• chrX-49076502-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001029896.2(WDR45):​c.364C>G​(p.Arg122Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,152 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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]

ENSG00000288053 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40663728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.364C>G	p.Arg122Gly	missense_variant	6/11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.367C>G	p.Arg123Gly	missense_variant	7/12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.364C>G	p.Arg122Gly	missense_variant	6/11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.131-557C>G		intron_variant		2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098152 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.;.;.;.;T;.;T;T;T;.;T;T;.;.;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;.;.;D;D;D;D;D;.;.;D;.;D;.;.;D;D;.
REVEL	Benign	0.28
Sift	Benign	0.31	T;.;.;T;T;T;T;T;.;.;T;.;T;.;.;T;T;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;.;.;.;.;.;T;.;.;.
Polyphen		0.39	B;B;.;P;B;P;B;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.52		Loss of MoRF binding (P = 0.0383);Loss of MoRF binding (P = 0.0383);Loss of MoRF binding (P = 0.0383);Loss of MoRF binding (P = 0.0383);.;.;Loss of MoRF binding (P = 0.0383);.;.;.;.;Loss of MoRF binding (P = 0.0383);.;.;Loss of MoRF binding (P = 0.0383);.;Loss of MoRF binding (P = 0.0383);.;
MVP		0.78
MPC		1.0
ClinPred		0.45	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs782643042; hg19: chrX-48934161;