Genetic Variant AXIN1:p.Arg803Arg (chr16-289493-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003502.4(AXIN1):c.2409C>T(p.Arg803Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,612,952 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 10 hom. )

Consequence

AXIN1
NM_003502.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.15

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104574460

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.027).

BP6

Variant 16-289493-G-A is Benign according to our data. Variant chr16-289493-G-A is described in ClinVar as Benign. ClinVar VariationId is 787969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00815 (1241/152328) while in subpopulation AFR AF = 0.0279 (1158/41562). AF 95% confidence interval is 0.0265. There are 13 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1241 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AXIN1	NM_003502.4	MANE Select	c.2409C>T	p.Arg803Arg	synonymous	Exon 10 of 11	NP_003493.1	A0A0S2Z4R0
AXIN1	NM_181050.3		c.2301C>T	p.Arg767Arg	synonymous	Exon 9 of 10	NP_851393.1	O15169-2
AXIN1	NR_134879.2		n.2640C>T		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.2409C>T	p.Arg803Arg	synonymous	Exon 10 of 11	ENSP00000262320.3	O15169-1
AXIN1	ENST00000354866.7	TSL:1	c.2301C>T	p.Arg767Arg	synonymous	Exon 9 of 10	ENSP00000346935.3	O15169-2
AXIN1	ENST00000957925.1		c.2424C>T	p.Arg808Arg	synonymous	Exon 10 of 11	ENSP00000627984.1

Frequencies

GnomAD3 genomes

AF:

0.00815

AC:

1240

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0279

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00232

AC:

580

AN:

250010

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.0296

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000907

AC:

1325

AN:

1460624

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

557

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.0276

AC:

923

AN:

33480

American (AMR)

AF:

0.00174

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000383

AC:

AN:

52192

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1111992

Other (OTH)

AF:

0.00204

AC:

123

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

176

263

351

439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00815

AC:

1241

AN:

152328

Hom.:

Cov.:

AF XY:

0.00813

AC XY:

606

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0279

AC:

1158

AN:

41562

American (AMR)

AF:

0.00340

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68038

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00493

Hom.:

Bravo

AF:

0.00945

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.070

(source)

DANN

Benign

0.78

PhyloP100

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over