2-74423366-C-A

Variant names:

• chr2-74423366-C-A
• NM_032118.4:c.333C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032118.4(WDR54):​c.333C>A​(p.Asp111Glu) variant causes a missense 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. 16/22 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: 0.0200
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055728614).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032118.4. 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
	WDR54	NM_032118.4	MANE Select	c.333C>A	p.Asp111Glu	missense	Exon 4 of 10	NP_115494.1	Q9H977-1
	WDR54	NM_001320823.2		c.378C>A	p.Asp126Glu	missense	Exon 4 of 10	NP_001307752.1	Q9H977-4
	WDR54	NM_001320824.2		c.333C>A	p.Asp111Glu	missense	Exon 4 of 10	NP_001307753.1	Q9H977-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR54	ENST00000348227.4	TSL:1 MANE Select	c.333C>A	p.Asp111Glu	missense	Exon 4 of 10	ENSP00000006526.6	Q9H977-1
	WDR54	ENST00000465134.5	TSL:1	n.1237C>A		non_coding_transcript_exon	Exon 2 of 7
	WDR54	ENST00000861017.1		c.333C>A	p.Asp111Glu	missense	Exon 4 of 10	ENSP00000531076.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.020
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.12
Sift	Benign	0.75	T
Sift4G	Benign	0.26	T
Polyphen		0.0030	B
Vest4		0.50
MutPred		0.35		Loss of sheet (P = 0.0817)
MVP		0.25
MPC		0.21
ClinPred		0.18	T
GERP RS		2.9
Varity_R		0.10
gMVP		0.16
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

hg19: chr2-74650493;