rs1805105

Positions:

• chr16-346264-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 402405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-346264-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN1	NM_003502.4	c.762T>C	p.Asp254Asp	synonymous_variant	2/11	ENST00000262320.8	NP_003493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN1	ENST00000262320.8	c.762T>C	p.Asp254Asp	synonymous_variant	2/11	1	NM_003502.4	ENSP00000262320.3
AXIN1	ENST00000354866.7	c.762T>C	p.Asp254Asp	synonymous_variant	2/10	1		ENSP00000346935.3
AXIN1	ENST00000461023.5	n.59T>C		non_coding_transcript_exon_variant	1/8	2
AXIN1	ENST00000481769.1	n.305+6105T>C		intron_variant		3

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

GnomAD3 exomes AF: 0.607 AC: 152675 AN: 251444 Hom.: 48902 AF XY: 0.618 AC XY: 83919 AN XY: 135894

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 SAS exome AF: 0.740

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

Gnomad4 AFR exome AF: 0.873

Gnomad4 AMR exome AF: 0.455

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.739

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.657

Gnomad4 OTH exome AF: 0.631

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

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.648

Gnomad4 OTH AF: 0.624

Alfa AF: 0.637 Hom.: 45129

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.043
DANN	Benign	0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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