Genetic Variant AXIN1:p.Ala609Ala (chr16-297184-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_003502.4(AXIN1):c.1827T>C(p.Ala609Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,610,218 control chromosomes in the GnomAD database, including 41,284 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 0.25 ( 5539 hom., cov: 33)

Exomes 𝑓: 0.21 ( 35745 hom. )

Consequence

AXIN1
NM_003502.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.60

Publications

30 publications found

Variant links:

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

AXIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP7

Synonymous conserved (PhyloP=-5.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN1	NM_003502.4 link	c.1827T>C	p.Ala609Ala	synonymous_variant	Exon 7 of 11	ENST00000262320.8	NP_003493.1	O15169-1A0A0S2Z4R0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AXIN1	ENST00000262320.8 link	c.1827T>C	p.Ala609Ala	synonymous_variant	Exon 7 of 11	1	NM_003502.4	ENSP00000262320.3	O15169-1
AXIN1	ENST00000354866.7 link	c.1827T>C	p.Ala609Ala	synonymous_variant	Exon 7 of 10	1		ENSP00000346935.3	O15169-2
AXIN1	ENST00000461023.5 link	n.1124T>C		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38323

AN:

151968

Hom.:

5526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.392

Gnomad AMI

AF:

0.414

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.195

Gnomad EAS

AF:

0.0609

Gnomad SAS

AF:

0.0910

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.229

GnomAD2 exomes

AF:

0.189

AC:

47156

AN:

249100

AF XY:

0.185

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.0992

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.0566

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.213

AC:

310991

AN:

1458132

Hom.:

35745

Cov.:

AF XY:

0.210

AC XY:

152543

AN XY:

725602

show subpopulations

African (AFR)

AF:

0.405

AC:

13549

AN:

33480

American (AMR)

AF:

0.108

AC:

4815

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5192

AN:

26128

East Asian (EAS)

AF:

0.0757

AC:

3004

AN:

39696

South Asian (SAS)

AF:

0.0967

AC:

8339

AN:

86258

European-Finnish (FIN)

AF:

0.212

AC:

10570

AN:

49790

Middle Eastern (MID)

AF:

0.216

AC:

1247

AN:

5768

European-Non Finnish (NFE)

AF:

0.226

AC:

251838

AN:

1111930

Other (OTH)

AF:

0.206

AC:

12437

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

14825

29650

44475

59300

74125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8532

17064

25596

34128

42660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.252

AC:

38378

AN:

152086

Hom.:

5539

Cov.:

AF XY:

0.245

AC XY:

18226

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.392

AC:

16266

AN:

41470

American (AMR)

AF:

0.157

AC:

2398

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

677

AN:

3472

East Asian (EAS)

AF:

0.0610

AC:

315

AN:

5162

South Asian (SAS)

AF:

0.0919

AC:

443

AN:

4822

European-Finnish (FIN)

AF:

0.197

AC:

2084

AN:

10580

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15274

AN:

67976

Other (OTH)

AF:

0.226

AC:

479

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1411

2821

4232

5642

7053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

390

780

1170

1560

1950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.234

Hom.:

6783

Bravo

AF:

0.260

Asia WGS

AF:

0.0990

AC:

347

AN:

3478

EpiCase

AF:

0.214

EpiControl

AF:

0.217

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.033

(source)

DANN

Benign

0.23

PhyloP100

-5.6

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over