2-74423924-A-G

Variant names:

• chr2-74423924-A-G
• NM_032118.4:c.476A>G

Variant summary

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

The NM_032118.4(WDR54):​c.476A>G​(p.Glu159Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR54 NM_032118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

Genes affected

WDR54 (HGNC:25770): (WD repeat domain 54) Enables protein homodimerization activity. Involved in negative regulation of receptor internalization; regulation of MAPK cascade; and regulation of epidermal growth factor receptor signaling pathway. Located in vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2477271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR54	NM_032118.4	c.476A>G	p.Glu159Gly	missense_variant	Exon 6 of 10	ENST00000348227.4	NP_115494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR54	ENST00000348227.4	c.476A>G	p.Glu159Gly	missense_variant	Exon 6 of 10	1	NM_032118.4	ENSP00000006526.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476A>G (p.E159G) alteration is located in exon 6 (coding exon 5) of the WDR54 gene. This alteration results from a A to G substitution at nucleotide position 476, causing the glutamic acid (E) at amino acid position 159 to be replaced by a glycine (G). 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	0.20
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.83	.;.;P
Vest4		0.50
MutPred		0.40		.;.;Loss of stability (P = 0.0104);
MVP		0.56
MPC		0.39
ClinPred		0.72	D
GERP RS		5.2
Varity_R		0.089
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74651051;