rs201384117

Positions:

• chrX-49075972-T-A
• chrX-49075972-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001029896.2(WDR45):​c.437-27A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,140,106 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 13 hem.)
• Consequence: WDR45 NM_001029896.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (MetaRNN=0.032790303).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR45	NM_001029896.2	c.437-27A>T		intron_variant		ENST00000376372.9
WDR45	NM_007075.4	c.440-27A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR45	ENST00000376372.9	c.437-27A>T		intron_variant		1	NM_001029896.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000275 AC: 3 AN: 109261 Hom.: 0 Cov.: 23 AF XY: 0.0000627 AC XY: 2 AN XY: 31903

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000191

Gnomad OTH AF: 0.000680

GnomAD3 exomes AF: 0.0000555 AC: 9 AN: 162303 Hom.: 0 AF XY: 0.0000588 AC XY: 3 AN XY: 51035

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000407

Gnomad NFE exome AF: 0.0000287

Gnomad OTH exome AF: 0.000243

GnomAD4 exome AF: 0.0000369 AC: 38 AN: 1030845 Hom.: 0 Cov.: 25 AF XY: 0.0000424 AC XY: 13 AN XY: 306383

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000802

Gnomad4 NFE exome AF: 0.00000637

Gnomad4 OTH exome AF: 0.0000228

GnomAD4 genome AF: 0.0000275 AC: 3 AN: 109261 Hom.: 0 Cov.: 23 AF XY: 0.0000627 AC XY: 2 AN XY: 31903

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000173

Gnomad4 NFE AF: 0.0000191

Gnomad4 OTH AF: 0.000680

Alfa AF: 0.000198 Hom.: 1

ExAC AF: 0.0000661 AC: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.76
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.17	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PROVEAN	Benign	0.15	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.75	T;.;.
Vest4		0.23
MutPred		0.40		Loss of ubiquitination at K145 (P = 0.0508);.;Loss of ubiquitination at K145 (P = 0.0508);
MVP		0.18
ClinPred		0.0071	T
GERP RS		-2.3
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201384117; hg19: chrX-48933631;