chrX-118409570-G-T

Position:

• chrX-118409570-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_019045.5(WDR44):​c.1615G>T​(p.Ala539Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,093,207 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes 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: 22)
  • Exomes 𝑓: 0.000011 (0 hom. 4 hem.)
• Consequence: WDR44 NM_019045.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

Genes affected

WDR44 (HGNC:30512): (WD repeat domain 44) This gene encodes a protein that interacts with the small GTPase rab11. A similar protein in rat binds the GTP-containing active form of rab11. This protein may play a role in endosome recycling. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31877074).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR44	NM_019045.5	c.1615G>T	p.Ala539Ser	missense_variant	11/20	ENST00000254029.8	NP_061918.3
WDR44	NM_001184965.2	c.1615G>T	p.Ala539Ser	missense_variant	11/20		NP_001171894.1
WDR44	NM_001184966.1	c.1540G>T	p.Ala514Ser	missense_variant	10/18		NP_001171895.1
WDR44	XM_011531353.4	c.1540G>T	p.Ala514Ser	missense_variant	10/19		XP_011529655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR44	ENST00000254029.8	c.1615G>T	p.Ala539Ser	missense_variant	11/20	1	NM_019045.5	ENSP00000254029.3
WDR44	ENST00000371825.7	c.1615G>T	p.Ala539Ser	missense_variant	11/20	1		ENSP00000360890.3
WDR44	ENST00000371848.3	c.1312G>T	p.Ala438Ser	missense_variant	8/18	1		ENSP00000360914.3
WDR44	ENST00000371822.9	c.1540G>T	p.Ala514Ser	missense_variant	10/18	2		ENSP00000360887.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000110 AC: 12 AN: 1093207 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 4 AN XY: 359057

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000399

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2024

The c.1615G>T (p.A539S) alteration is located in exon 11 (coding exon 11) of the WDR44 gene. This alteration results from a G to T substitution at nucleotide position 1615, causing the alanine (A) at amino acid position 539 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	.;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.062	T;D;T
Sift4G	Benign	0.075	T;T;T
Polyphen		0.88, 0.91	.;P;P
Vest4		0.38
MutPred		0.53		.;Gain of MoRF binding (P = 0.1);Gain of MoRF binding (P = 0.1);
MVP		0.40
MPC		1.1
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.45
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2056995704; hg19: chrX-117543533;