16-293484-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003502.4(AXIN1):c.2186+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,608,210 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: AXIN1 NM_003502.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00005777
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -3.84

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-293484-G-A is Benign according to our data. Variant chr16-293484-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1206002.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-293484-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2186+4C>T		splice_donor_region_variant, intron_variant		1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2186+4C>T		splice_donor_region_variant, intron_variant		1		P4
AXIN1	ENST00000457798.1	c.49+4C>T		splice_donor_region_variant, intron_variant		3
AXIN1	ENST00000461023.5	n.1487C>T		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00152 AC: 370 AN: 243746 Hom.: 2 AF XY: 0.00153 AC XY: 203 AN XY: 133112

Gnomad AFR exome AF: 0.00485

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.000899

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00167 AC: 2434 AN: 1455958 Hom.: 8 Cov.: 31 AF XY: 0.00164 AC XY: 1190 AN XY: 724386

Gnomad4 AFR exome AF: 0.00572

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74442

Gnomad4 AFR AF: 0.00464

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.00272 Hom.: 0

Bravo AF: 0.00287

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	AXIN1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.16
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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: rs145099978; hg19: chr16-343484; COSMIC: COSV51987128; COSMIC: COSV51987128;