16-288189-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003502.4(AXIN1):c.2522G>A(p.Arg841Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00913 in 1,613,706 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (11 hom., cov: 34)
  • Exomes 𝑓: 0.0093 (99 hom.)
• Consequence: AXIN1 NM_003502.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.87

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047746897).
• BP6: Variant 16-288189-C-T is Benign according to our data. Variant chr16-288189-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 774502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.2522G>A	p.Arg841Gln	missense_variant	11/11	ENST00000262320.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN1	ENST00000262320.8	c.2522G>A	p.Arg841Gln	missense_variant	11/11	1	NM_003502.4	A1
AXIN1	ENST00000354866.7	c.2414G>A	p.Arg805Gln	missense_variant	10/10	1		P4
AXIN1	ENST00000461023.5	n.5591G>A		non_coding_transcript_exon_variant	8/8	2
AXIN1	ENST00000457798.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00779 AC: 1186 AN: 152204 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00842 AC: 2111 AN: 250678 Hom.: 16 AF XY: 0.00856 AC XY: 1161 AN XY: 135672

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00927 AC: 13542 AN: 1461384 Hom.: 99 Cov.: 31 AF XY: 0.00921 AC XY: 6693 AN XY: 726984

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.00980

Gnomad4 OTH exome AF: 0.00768

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152322 Hom.: 11 Cov.: 34 AF XY: 0.00850 AC XY: 633 AN XY: 74476

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00828 Hom.: 2

Bravo AF: 0.00585

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00840 AC: 1020

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.00848

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Caudal duplication;C2239176:Hepatocellular carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 18, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T
Sift4G	Benign	0.30	T;T
Polyphen		1.0	D;D
Vest4		0.23
MVP		0.59
MPC		0.90
ClinPred		0.026	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.56

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: rs34015754; hg19: chr16-338189; COSMIC: COSV51989077; COSMIC: COSV51989077;