Genetic Variant WNT8A:p.Arg310Leu (chr5-138090892-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001300939.2(WNT8A):c.929G>T(p.Arg310Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WNT8A
NM_001300939.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.42

Variant links:

Genes affected

WNT8A (HGNC:12788): (Wnt family member 8A) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and may be implicated in development of early embryos as well as germ cell tumors. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2014]

WNT8A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT8A	NM_001300939.2 link	c.929G>T	p.Arg310Leu	missense_variant	Exon 5 of 5	ENST00000506684.6	NP_001287868.1	Q9H1J5D6RF47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNT8A	ENST00000506684.6 link	c.929G>T	p.Arg310Leu	missense_variant	Exon 5 of 5	1	NM_001300939.2	ENSP00000426653.1	D6RF47
WNT8A	ENST00000504809.5 link	c.929G>T	p.Arg310Leu	missense_variant	Exon 5 of 6	1		ENSP00000424809.1	D6RF94
WNT8A	ENST00000398754.1 link	c.875G>T	p.Arg292Leu	missense_variant	Exon 6 of 6	1		ENSP00000381739.1	Q9H1J5-1
WNT8A	ENST00000361560.6 link	n.875G>T		non_coding_transcript_exon_variant	Exon 6 of 8	1		ENSP00000354726.2	Q9H1J5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;.;D

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.44

.;.;N

PhyloP100

2.4

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.47

Sift

Benign

0.16

T;T;D

Sift4G

Benign

0.77

T;T;T

Polyphen

0.99

D;D;P

Vest4

0.34

MutPred

0.63

Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);.;

MVP

0.24

MPC

0.47

ClinPred

0.99

GERP RS

2.3

Varity_R

0.30

gMVP

0.73

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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5-138090892-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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