5-138090802-A-C

Position:

• chr5-138090802-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001300939.2(WNT8A):​c.839A>C​(p.Asn280Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WNT8A NM_001300939.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.90

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT8A	NM_001300939.2	c.839A>C	p.Asn280Thr	missense_variant	5/5	ENST00000506684.6	NP_001287868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT8A	ENST00000506684.6	c.839A>C	p.Asn280Thr	missense_variant	5/5	1	NM_001300939.2	ENSP00000426653.1
WNT8A	ENST00000504809.5	c.839A>C	p.Asn280Thr	missense_variant	5/6	1		ENSP00000424809.1
WNT8A	ENST00000398754.1	c.785A>C	p.Asn262Thr	missense_variant	6/6	1		ENSP00000381739.1
WNT8A	ENST00000361560.6	n.785A>C		non_coding_transcript_exon_variant	6/8	1		ENSP00000354726.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2024

The c.785A>C (p.N262T) alteration is located in exon 6 (coding exon 6) of the WNT8A gene. This alteration results from a A to C substitution at nucleotide position 785, causing the asparagine (N) at amino acid position 262 to be replaced by a threonine (T). 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.9	.;.;H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.76
MutPred		0.73		Loss of catalytic residue at N280 (P = 0.0312);Loss of catalytic residue at N280 (P = 0.0312);.;
MVP		0.61
MPC		0.92
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs977841556; hg19: chr5-137426491;