X-49075972-T-G

Variant names:

• chrX-49075972-T-G
• rs201384117
• NM_001029896.2:c.437-27A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001029896.2(WDR45):​c.437-27A>C variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 23)
• Consequence: WDR45 NM_001029896.2 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

ENSG00000288053 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (MetaRNN=0.075911134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR45	NM_001029896.2	c.437-27A>C		intron_variant	Intron 6 of 10	ENST00000376372.9	NP_001025067.1
WDR45	NM_007075.4	c.440-27A>C		intron_variant	Intron 7 of 11		NP_009006.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR45	ENST00000376372.9	c.437-27A>C		intron_variant	Intron 6 of 10	1	NM_001029896.2	ENSP00000365551.3
ENSG00000288053	ENST00000376358.4	c.131-27A>C		intron_variant	Intron 3 of 7	2		ENSP00000365536.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.9
DANN	Benign	0.67
DEOGEN2	Benign	0.0055	.;.;T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.16	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.0090
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.37	T;.;.
Vest4		0.19
MutPred		0.42		Gain of glycosylation at H148 (P = 0.0385);.;Gain of glycosylation at H148 (P = 0.0385);
MVP		0.17
ClinPred		0.021	T
GERP RS		-2.3
BranchPoint Hunter		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs201384117; hg19: chrX-48933631;