16-289499-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003502.4(AXIN1):c.2403G>A(p.Arg801=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00775 in 1,612,972 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (60 hom.)
• Consequence: AXIN1 NM_003502.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.163

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-289499-C-T is Benign according to our data. Variant chr16-289499-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 771011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.163 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN1	NM_003502.4	c.2403G>A	p.Arg801=	synonymous_variant	10/11	ENST00000262320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2403G>A	p.Arg801=	synonymous_variant	10/11	1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2295G>A	p.Arg765=	synonymous_variant	9/10	1		P4
AXIN1	ENST00000457798.1	c.159G>A	p.Arg53=	synonymous_variant	2/3	3
AXIN1	ENST00000461023.5	n.5472G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 780 AN: 152214 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00848

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00517 AC: 1294 AN: 250056 Hom.: 11 AF XY: 0.00491 AC XY: 666 AN XY: 135682

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00847

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00803 AC: 11725 AN: 1460640 Hom.: 60 Cov.: 33 AF XY: 0.00790 AC XY: 5738 AN XY: 726618

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00295

Gnomad4 NFE exome AF: 0.00963

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152332 Hom.: 6 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74484

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00848

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00782 Hom.: 3

Bravo AF: 0.00541

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Caudal duplication;C2239176:Hepatocellular carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 29, 2021

- -

AXIN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.9
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs113073289; hg19: chr16-339499; COSMIC: COSV99250540; COSMIC: COSV99250540;