X-48601956-T-G

Variant names:

• chrX-48601956-T-G
• NM_001347217.2:c.1004T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001347217.2(WDR13):​c.1004T>G​(p.Met335Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M335I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: WDR13 NM_001347217.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• Publications: 0 publications found

Genes affected

WDR13 (HGNC:14352): (WD repeat domain 13) 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. A similar protein in mouse is thought to be a negative regulator of the pancreatic beta cell proliferation. Mice lacking this gene exhibit increased pancreatic islet mass and higher serum insulin levels, and are mildly obese. [provided by RefSeq, Nov 2016]

WDR13 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347217.2. 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
	WDR13	NM_001347217.2	MANE Select	c.1004T>G	p.Met335Arg	missense	Exon 7 of 10	NP_001334146.1	Q9H1Z4-1
	WDR13	NM_017883.6		c.1004T>G	p.Met335Arg	missense	Exon 6 of 9	NP_060353.2
	WDR13	NM_001166426.3		c.728T>G	p.Met243Arg	missense	Exon 5 of 8	NP_001159898.1	Q9H1Z4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR13	ENST00000376729.10	TSL:5 MANE Select	c.1004T>G	p.Met335Arg	missense	Exon 7 of 10	ENSP00000365919.5	Q9H1Z4-1
	WDR13	ENST00000218056.9	TSL:1	c.1004T>G	p.Met335Arg	missense	Exon 6 of 9	ENSP00000218056.5	Q9H1Z4-1
	WDR13	ENST00000479279.5	TSL:1	n.1871T>G		non_coding_transcript_exon	Exon 5 of 8

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Benign	0.69
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.88	T
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Benign	0.64	T
Sift4G	Benign	0.11	T
Vest4		0.64
MutPred		0.66		Gain of MoRF binding (P = 0.0179)
MVP		0.97
MPC		1.6
ClinPred		0.83	D
GERP RS		5.4
gMVP		0.98
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

hg19: chrX-48460344;