16-288232-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003502.4(AXIN1):c.2479G>A(p.Val827Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AXIN1 NM_003502.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

Genes affected

AXIN1 (HGNC:903): (axin 1) This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin beta-1, glycogen synthase kinase 3 beta, protein phosphate 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN1	NM_003502.4	c.2479G>A	p.Val827Met	missense_variant	11/11	ENST00000262320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2479G>A	p.Val827Met	missense_variant	11/11	1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2371G>A	p.Val791Met	missense_variant	10/10	1		P4
AXIN1	ENST00000457798.1	c.293G>A	p.Ser98Asn	missense_variant	3/3	3
AXIN1	ENST00000461023.5	n.5548G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Jan 20, 2023

The c.2479G>A (p.V827M) alteration is located in exon 11 (coding exon 10) of the AXIN1 gene. This alteration results from a G to A substitution at nucleotide position 2479, causing the valine (V) at amino acid position 827 to be replaced by a methionine (M). 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	Uncertain	0.36
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	29
Dann	Benign	0.93
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.67	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.46		Loss of methylation at K826 (P = 0.0182);.;
MVP		0.80
MPC		1.1
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.56
gMVP		0.46

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: rs2052441220; hg19: chr16-338232;