16-289493-G-A

Position:

• chr16-289493-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003502.4(AXIN1):​c.2409C>T​(p.Arg803=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,612,952 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (10 hom.)
• Consequence: AXIN1 NM_003502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.15

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=-0.82).
• BP6: Variant 16-289493-G-A is Benign according to our data. Variant chr16-289493-G-A is described in ClinVar as [Benign]. Clinvar id is 787969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00815 (1241/152328) while in subpopulation AFR AF= 0.0279 (1158/41562). AF 95% confidence interval is 0.0265. There are 13 homozygotes in gnomad4. There are 606 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN1	NM_003502.4	c.2409C>T	p.Arg803=	synonymous_variant	10/11	ENST00000262320.8	NP_003493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN1	ENST00000262320.8	c.2409C>T	p.Arg803=	synonymous_variant	10/11	1	NM_003502.4	ENSP00000262320	A1
AXIN1	ENST00000354866.7	c.2301C>T	p.Arg767=	synonymous_variant	9/10	1		ENSP00000346935	P4
AXIN1	ENST00000457798.1	c.165C>T	p.Arg55=	synonymous_variant	2/3	3		ENSP00000416835
AXIN1	ENST00000461023.5	n.5478C>T		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 1240 AN: 152210 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00232 AC: 580 AN: 250010 Hom.: 7 AF XY: 0.00160 AC XY: 217 AN XY: 135670

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000907 AC: 1325 AN: 1460624 Hom.: 10 Cov.: 33 AF XY: 0.000767 AC XY: 557 AN XY: 726602

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152328 Hom.: 13 Cov.: 33 AF XY: 0.00813 AC XY: 606 AN XY: 74496

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00474 Hom.: 3

Bravo AF: 0.00945

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.070
DANN	Benign	0.78
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: rs61753369; hg19: chr16-339493; COSMIC: COSV104574460; COSMIC: COSV104574460;