16-289579-C-T

Position:

chr16-289579-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003502.4(AXIN1):c.2323G>A(p.Gly775Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,612,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

AXIN1
NM_003502.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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:

AXIN1 (HGNC:):

AXIN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1208688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN1	NM_003502.4 linkuse as main transcript	c.2323G>A	p.Gly775Arg	missense_variant	10/11	ENST00000262320.8	NP_003493.1	O15169-1A0A0S2Z4R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AXIN1	ENST00000262320.8 linkuse as main transcript	c.2323G>A	p.Gly775Arg	missense_variant	10/11	1	NM_003502.4	ENSP00000262320.3	O15169-1
AXIN1	ENST00000354866.7 linkuse as main transcript	c.2215G>A	p.Gly739Arg	missense_variant	9/10	1		ENSP00000346935.3	O15169-2
AXIN1	ENST00000457798.1 linkuse as main transcript	c.76G>A	p.Gly26Arg	missense_variant	2/3	3		ENSP00000416835.1	H0Y830
AXIN1	ENST00000461023.5 linkuse as main transcript	n.5392G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249306

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000186

AC:

271

AN:

1460590

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

726606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.2323G>A (p.G775R) alteration is located in exon 10 (coding exon 9) of the AXIN1 gene. This alteration results from a G to A substitution at nucleotide position 2323, causing the glycine (G) at amino acid position 775 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.87

D;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

L;.

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.87

N;N

REVEL

Benign

0.12

Sift

Benign

0.069

T;T

Sift4G

Benign

0.23

T;D

Polyphen

0.98

D;B

Vest4

0.36

MutPred

0.23

Gain of MoRF binding (P = 0.0274);.;

MVP

0.35

MPC

0.44

ClinPred

0.020

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.33

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