16-289499-C-T

Variant names:

• chr16-289499-C-T
• rs113073289
• NM_003502.4:c.2403G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP6_Very_Strong BP7 BS2

The NM_003502.4(AXIN1):​c.2403G>A​(p.Arg801Arg) 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. 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:5
• Conservation: PhyloP100: 0.163
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• caudal duplication

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP6: Variant 16-289499-C-T is Benign according to our data. Variant chr16-289499-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 AC in GnomAd4 at 780 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	NM_003502.4	MANE Select	c.2403G>A	p.Arg801Arg	synonymous	Exon 10 of 11	NP_003493.1	A0A0S2Z4R0
	AXIN1	NM_181050.3		c.2295G>A	p.Arg765Arg	synonymous	Exon 9 of 10	NP_851393.1	O15169-2
	AXIN1	NR_134879.2		n.2634G>A		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.2403G>A	p.Arg801Arg	synonymous	Exon 10 of 11	ENSP00000262320.3	O15169-1
	AXIN1	ENST00000354866.7	TSL:1	c.2295G>A	p.Arg765Arg	synonymous	Exon 9 of 10	ENSP00000346935.3	O15169-2
	AXIN1	ENST00000957925.1		c.2418G>A	p.Arg806Arg	synonymous	Exon 10 of 11	ENSP00000627984.1

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

GnomAD2 exomes AF: 0.00517 AC: 1294 AN: 250056 AF XY: 0.00491

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 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

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00246 AC: 110 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00295 AC: 154 AN: 52206

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00963 AC: 10714 AN: 1111994

Other (OTH) AF: 0.00619 AC: 374 AN: 60378

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

African (AFR) AF: 0.00152 AC: 63 AN: 41584

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00848 AC: 577 AN: 68026

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	AXIN1-related disorder (1)
-	-	1	Caudal duplication;C2239176:Hepatocellular carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.9
DANN	Benign	0.72
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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