16-299293-A-G

Variant names:

• chr16-299293-A-G
• rs214246
• NM_003502.4:c.1255-1042T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003502.4(AXIN1):​c.1255-1042T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 951,116 control chromosomes in the GnomAD database, including 124,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (26922 hom., cov: 34)
  • Exomes 𝑓: 0.49 (97264 hom.)
• Consequence: AXIN1 NM_003502.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.416
• Publications: 8 publications found

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]

AXIN1 Gene-Disease associations (from GenCC):

• caudal duplication

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	NM_003502.4	MANE Select	c.1255-1042T>C		intron	N/A	NP_003493.1
	AXIN1	NM_181050.3		c.1255-1042T>C		intron	N/A	NP_851393.1
	AXIN1	NR_134879.2		n.1594-1042T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.1255-1042T>C		intron	N/A	ENSP00000262320.3
	AXIN1	ENST00000354866.7	TSL:1	c.1255-1042T>C		intron	N/A	ENSP00000346935.3
	AXIN1	ENST00000461023.5	TSL:2	n.552-1042T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85960 AN: 152078 Hom.: 26867 Cov.: 34

Gnomad AFR AF: 0.844

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.520

GnomAD4 exome AF: 0.490 AC: 391172 AN: 798920 Hom.: 97264 AF XY: 0.490 AC XY: 181347 AN XY: 369928

African (AFR) AF: 0.884 AC: 13201 AN: 14926

American (AMR) AF: 0.328 AC: 312 AN: 952

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 2241 AN: 4970

East Asian (EAS) AF: 0.321 AC: 1118 AN: 3486

South Asian (SAS) AF: 0.580 AC: 9165 AN: 15808

European-Finnish (FIN) AF: 0.388 AC: 104 AN: 268

Middle Eastern (MID) AF: 0.526 AC: 820 AN: 1558

European-Non Finnish (NFE) AF: 0.481 AC: 351343 AN: 730846

Other (OTH) AF: 0.493 AC: 12868 AN: 26106

GnomAD4 genome AF: 0.566 AC: 86070 AN: 152196 Hom.: 26922 Cov.: 34 AF XY: 0.560 AC XY: 41655 AN XY: 74402

African (AFR) AF: 0.844 AC: 35075 AN: 41538

American (AMR) AF: 0.384 AC: 5871 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3470

East Asian (EAS) AF: 0.334 AC: 1729 AN: 5180

South Asian (SAS) AF: 0.600 AC: 2896 AN: 4828

European-Finnish (FIN) AF: 0.421 AC: 4452 AN: 10578

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32669 AN: 67994

Other (OTH) AF: 0.524 AC: 1107 AN: 2112

Alfa AF: 0.493 Hom.: 32619

Bravo AF: 0.570

Asia WGS AF: 0.542 AC: 1882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs214246; hg19: chr16-349293; COSMIC: COSV51985050;