16-346264-A-G

Variant names:

• chr16-346264-A-G
• rs1805105
• NM_003502.4:c.762T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003502.4(AXIN1):​c.762T>C​(p.Asp254Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,613,910 control chromosomes in the GnomAD database, including 346,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36887 hom., cov: 33)
  • Exomes 𝑓: 0.65 (309816 hom.)
• Consequence: AXIN1 NM_003502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.19
• Publications: 51 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 16-346264-A-G is Benign according to our data. Variant chr16-346264-A-G is described in ClinVar as Benign. ClinVar VariationId is 402405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	NM_003502.4	MANE Select	c.762T>C	p.Asp254Asp	synonymous	Exon 2 of 11	NP_003493.1
	AXIN1	NM_181050.3		c.762T>C	p.Asp254Asp	synonymous	Exon 2 of 10	NP_851393.1
	AXIN1	NR_134879.2		n.1198T>C		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.762T>C	p.Asp254Asp	synonymous	Exon 2 of 11	ENSP00000262320.3
	AXIN1	ENST00000354866.7	TSL:1	c.762T>C	p.Asp254Asp	synonymous	Exon 2 of 10	ENSP00000346935.3
	AXIN1	ENST00000461023.5	TSL:2	n.59T>C		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103838 AN: 151952 Hom.: 36834 Cov.: 33

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.621

GnomAD2 exomes AF: 0.607 AC: 152675 AN: 251444 AF XY: 0.618

Gnomad AFR exome AF: 0.874

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.646 AC: 944285 AN: 1461840 Hom.: 309816 Cov.: 80 AF XY: 0.649 AC XY: 471621 AN XY: 727218

African (AFR) AF: 0.873 AC: 29233 AN: 33480

American (AMR) AF: 0.455 AC: 20347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 13402 AN: 26136

East Asian (EAS) AF: 0.343 AC: 13625 AN: 39700

South Asian (SAS) AF: 0.739 AC: 63737 AN: 86258

European-Finnish (FIN) AF: 0.609 AC: 32510 AN: 53374

Middle Eastern (MID) AF: 0.559 AC: 3226 AN: 5768

European-Non Finnish (NFE) AF: 0.657 AC: 730069 AN: 1112004

Other (OTH) AF: 0.631 AC: 38136 AN: 60396

GnomAD4 genome AF: 0.684 AC: 103951 AN: 152070 Hom.: 36887 Cov.: 33 AF XY: 0.680 AC XY: 50537 AN XY: 74310

African (AFR) AF: 0.861 AC: 35746 AN: 41530

American (AMR) AF: 0.564 AC: 8608 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1758 AN: 3472

East Asian (EAS) AF: 0.312 AC: 1605 AN: 5144

South Asian (SAS) AF: 0.747 AC: 3590 AN: 4808

European-Finnish (FIN) AF: 0.613 AC: 6473 AN: 10560

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44024 AN: 67970

Other (OTH) AF: 0.624 AC: 1316 AN: 2110

Alfa AF: 0.652 Hom.: 89853

Bravo AF: 0.677

Asia WGS AF: 0.592 AC: 2055 AN: 3478

EpiCase AF: 0.627

EpiControl AF: 0.627

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.043
DANN	Benign	0.24
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs1805105; hg19: chr16-396264; COSMIC: COSV51987760;