X-49075636-G-T

Variant names:

• chrX-49075636-G-T
• rs387907332
• NM_001029896.2:c.634C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001029896.2(WDR45):​c.634C>A​(p.Gln212Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 2 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• 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 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001029896.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26035154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.634C>A	p.Gln212Lys	missense_variant	Exon 8 of 11	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.637C>A	p.Gln213Lys	missense_variant	Exon 9 of 12		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.634C>A	p.Gln212Lys	missense_variant	Exon 8 of 11	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.328C>A	p.Gln110Lys	missense_variant	Exon 5 of 8	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098178 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363534

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842095

Other (OTH) AF: 0.00 AC: 0 AN: 46092

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0071	T;T;.;T;T;.;T;.;.;.;T;.;T;.;T;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;T;D;D;.;T;T;D;T;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.73	.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;N;.;.;.;.;.;N;N;N;N;N;.;.;.;.
REVEL	Benign	0.073
Sift	Benign	0.090	T;T;.;.;.;.;.;T;T;T;T;T;.;.;.;.
Sift4G	Benign	0.75	T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.041	B;B;.;B;.;.;.;B;B;B;B;B;.;.;.;.
Vest4		0.20
MutPred		0.40		.;Gain of ubiquitination at Q212 (P = 0.0128);.;Gain of ubiquitination at Q212 (P = 0.0128);.;Gain of ubiquitination at Q212 (P = 0.0128);.;.;.;.;Gain of ubiquitination at Q212 (P = 0.0128);.;.;.;.;.;
MVP		0.54
MPC		1.8
ClinPred		0.65	D
GERP RS		3.8
PromoterAI		0.022	Neutral
Varity_R		0.35
gMVP		0.51
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs387907332; hg19: chrX-48933295;