Genetic Variant AXIN1:p.Asp843Glu (chr16-288182-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003502.4(AXIN1):c.2529C>G(p.Asp843Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

AXIN1
NM_003502.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.30

Variant links:

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]

AXIN1 links:

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ACMG classification

Classification made for transcript

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, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN1	NM_003502.4 link	c.2529C>G	p.Asp843Glu	missense_variant	Exon 11 of 11	ENST00000262320.8	NP_003493.1	O15169-1A0A0S2Z4R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AXIN1	ENST00000262320.8 link	c.2529C>G	p.Asp843Glu	missense_variant	Exon 11 of 11	1	NM_003502.4	ENSP00000262320.3	O15169-1
AXIN1	ENST00000354866.7 link	c.2421C>G	p.Asp807Glu	missense_variant	Exon 10 of 10	1		ENSP00000346935.3	O15169-2
AXIN1	ENST00000461023.5 link	n.5598C>G		non_coding_transcript_exon_variant	Exon 8 of 8	2
AXIN1	ENST00000457798.1 link	c.*34C>G		downstream_gene_variant		3		ENSP00000416835.1	H0Y830

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250794

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461370

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2529C>G (p.D843E) alteration is located in exon 11 (coding exon 10) of the AXIN1 gene. This alteration results from a C to G substitution at nucleotide position 2529, causing the aspartic acid (D) at amino acid position 843 to be replaced by a glutamic acid (E). 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

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

1.1

DANN

Benign

0.95

DEOGEN2

Uncertain

0.63

D;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.39

Sift

Benign

0.11

T;T

Sift4G

Benign

0.080

T;T

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.70

Gain of disorder (P = 0.0623);.;

MVP

0.45

MPC

1.1

ClinPred

0.67

GERP RS

-8.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over