Genetic Variant WDR54:p.Gly212Arg (chr2-74424974-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032118.4(WDR54):c.634G>C(p.Gly212Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

WDR54
NM_032118.4 missense, splice_region

Scores

Splicing: ADA: 0.9717

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.95

Publications

0 publications found

Variant links:

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]

WDR54 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR54	NM_032118.4 link	c.634G>C	p.Gly212Arg	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000348227.4	NP_115494.1	Q9H977-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR54	ENST00000348227.4 link	c.634G>C	p.Gly212Arg	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_032118.4	ENSP00000006526.6		Q9H977-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112004

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.634G>C (p.G212R) alteration is located in exon 7 (coding exon 6) of the WDR54 gene. This alteration results from a G to C substitution at nucleotide position 634, causing the glycine (G) at amino acid position 212 to be replaced by an arginine (R). 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

0.25

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L

PhyloP100

8.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.21

Sift

Benign

0.055

T;T

Sift4G

Uncertain

0.036

D;T

Polyphen

0.80

.;P

Vest4

0.71

MutPred

0.67

.;Loss of catalytic residue at V213 (P = 0.0296);

MVP

0.44

MPC

0.79

ClinPred

0.93

GERP RS

5.0

Varity_R

0.27

gMVP

0.53

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over