16-293481-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003502.4(AXIN1):c.2186+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,607,918 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: AXIN1 NM_003502.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002675
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.764

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-293481-G-A is Benign according to our data. Variant chr16-293481-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 446041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0116 (16841/1455632) while in subpopulation SAS AF= 0.0164 (1414/86166). AF 95% confidence interval is 0.0157. There are 121 homozygotes in gnomad4_exome. There are 8542 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN1	NM_003502.4	c.2186+7C>T		splice_region_variant, intron_variant		ENST00000262320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2186+7C>T		splice_region_variant, intron_variant		1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2186+7C>T		splice_region_variant, intron_variant		1		P4
AXIN1	ENST00000457798.1	c.49+7C>T		splice_region_variant, intron_variant		3
AXIN1	ENST00000461023.5	n.1490C>T		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152168 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00716

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00945 AC: 2297 AN: 242988 Hom.: 16 AF XY: 0.0101 AC XY: 1343 AN XY: 132808

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00914

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0116 AC: 16841 AN: 1455632 Hom.: 121 Cov.: 31 AF XY: 0.0118 AC XY: 8542 AN XY: 724226

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.00824

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00845 AC: 1287 AN: 152286 Hom.: 11 Cov.: 32 AF XY: 0.00829 AC XY: 617 AN XY: 74454

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00716

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0100 Hom.: 3

Bravo AF: 0.00775

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	AXIN1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 27, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.3
Dann	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.0020
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: rs189357878; hg19: chr16-343481;