16-291182-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003502.4(AXIN1):c.2294+8C>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 0.0284 in 1,572,316 control chromosomes in the GnomAD database, including 756 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (62 hom., cov: 33)
  • Exomes 𝑓: 0.029 (694 hom.)
• Consequence: AXIN1 NM_003502.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009310
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-291182-G-A is Benign according to our data. Variant chr16-291182-G-A is described in ClinVar as [Benign]. Clinvar id is 3056732.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0235 (3578/152300) while in subpopulation NFE AF= 0.0327 (2221/68006). AF 95% confidence interval is 0.0315. There are 62 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN1	NM_003502.4	c.2294+8C>T		splice_region_variant, intron_variant		ENST00000262320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2294+8C>T		splice_region_variant, intron_variant		1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2187-1575C>T		intron_variant		1		P4
AXIN1	ENST00000457798.1	c.50-1575C>T		intron_variant		3
AXIN1	ENST00000461023.5	n.3789C>T		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3582 AN: 152182 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0243 AC: 4482 AN: 184600 Hom.: 90 AF XY: 0.0239 AC XY: 2372 AN XY: 99042

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.0000700

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0290 AC: 41110 AN: 1420016 Hom.: 694 Cov.: 31 AF XY: 0.0284 AC XY: 19986 AN XY: 702600

Gnomad4 AFR exome AF: 0.00324

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00919

Gnomad4 FIN exome AF: 0.0601

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0235 AC: 3578 AN: 152300 Hom.: 62 Cov.: 33 AF XY: 0.0244 AC XY: 1820 AN XY: 74460

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0594

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0233 Hom.: 40

Bravo AF: 0.0196

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AXIN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	4.7
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.010
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: rs118063900; hg19: chr16-341182;