NM_032118.4:c.22A>T

Variant names:

• chr2-74422175-A-T
• rs1189065413
• NM_032118.4:c.22A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032118.4(WDR54):​c.22A>T​(p.Ile8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR54 NM_032118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.507
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25590822).

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.22A>T	p.Ile8Phe	missense	Exon 2 of 10	NP_115494.1	Q9H977-1
	WDR54	NM_001320823.2		c.67A>T	p.Ile23Phe	missense	Exon 2 of 10	NP_001307752.1	Q9H977-4
	WDR54	NM_001320824.2		c.22A>T	p.Ile8Phe	missense	Exon 2 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.22A>T	p.Ile8Phe	missense	Exon 2 of 10	ENSP00000006526.6	Q9H977-1
	WDR54	ENST00000465134.5	TSL:1	n.432A>T		non_coding_transcript_exon	Exon 1 of 7
	WDR54	ENST00000861017.1		c.22A>T	p.Ile8Phe	missense	Exon 2 of 10	ENSP00000531076.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461004 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726806

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60330

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	0.12
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.51
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.60	P
Vest4		0.55
MutPred		0.40		Gain of methylation at R11 (P = 0.0714)
MVP		0.14
MPC		0.40
ClinPred		0.86	D
GERP RS		1.3
PromoterAI		0.053	Neutral
Varity_R		0.31
gMVP		0.64
Mutation Taster		=71/29	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

dbSNP: rs1189065413; hg19: chr2-74649302;