Genetic Variant WWC1:p.Ser33Arg (chr5-168292251-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015238.3(WWC1):c.99C>A(p.Ser33Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S33G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WWC1
NM_015238.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.79

Publications

1 publications found

Variant links:

Genes affected

WWC1 (HGNC:29435): (WW and C2 domain containing 1) The protein encoded by this gene is a cytoplasmic phosphoprotein that interacts with PRKC-zeta and dynein light chain-1. Alleles of this gene have been found that enhance memory in some individuals. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

WWC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015238.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WWC1	NM_015238.3	MANE Select	c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	NP_056053.1	Q8IX03-1
WWC1	NM_001161661.2		c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	NP_001155133.1	Q8IX03-2
WWC1	NM_001161662.2		c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	NP_001155134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WWC1	ENST00000265293.9	TSL:1 MANE Select	c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	ENSP00000265293.4	Q8IX03-1
WWC1	ENST00000917779.1		c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	ENSP00000587838.1
WWC1	ENST00000917783.1		c.99C>A	p.Ser33Arg	missense	Exon 1 of 23	ENSP00000587842.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718806

African (AFR)

AF:

0.00

AC:

AN:

33108

American (AMR)

AF:

0.00

AC:

AN:

43418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25700

East Asian (EAS)

AF:

0.00

AC:

AN:

39036

South Asian (SAS)

AF:

0.00

AC:

AN:

83514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105840

Other (OTH)

AF:

0.00

AC:

AN:

59770

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.1

PhyloP100

1.8

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.77

MutPred

0.61

Gain of MoRF binding (P = 0.0193)

MVP

0.74

MPC

1.0

ClinPred

0.94

GERP RS

4.2

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.67

gMVP

0.67

Mutation Taster

=37/63

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over