Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003502.4(AXIN1):c.2186+7C>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 0.0113 in 1,607,918 control chromosomes in the GnomAD database, including 132 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 11 hom., cov: 32)

Exomes 𝑓: 0.012 ( 121 hom. )

Consequence

AXIN1
NM_003502.4 splice_region, intron

Scores

Splicing: ADA: 0.0002675

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.764

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 16-293481-G-A is Benign according to our data. Variant chr16-293481-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0116 (16841/1455632) while in subpopulation SAS AF = 0.0164 (1414/86166). AF 95% confidence interval is 0.0157. There are 121 homozygotes in GnomAdExome4. There are 8542 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1287 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	Effect	Exon Rank	Protein
AXIN1	NM_003502.4	MANE Select	c.2186+7C>T	splice_region intron	N/A	NP_003493.1
AXIN1	NM_181050.3		c.2186+7C>T	splice_region intron	N/A	NP_851393.1
AXIN1	NR_134879.2		n.2525+7C>T	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.2186+7C>T	splice_region intron	N/A	ENSP00000262320.3
AXIN1	ENST00000354866.7	TSL:1	c.2186+7C>T	splice_region intron	N/A	ENSP00000346935.3
AXIN1	ENST00000461023.5	TSL:2	n.1490C>T	non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1286

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00961

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.00716

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00945

AC:

2297

AN:

242988

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00602

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00914

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0116

AC:

16841

AN:

1455632

Hom.:

121

Cov.:

AF XY:

0.0118

AC XY:

8542

AN XY:

724226

show subpopulations

African (AFR)

AF:

0.00174

AC:

AN:

33402

American (AMR)

AF:

0.00624

AC:

279

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

319

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0164

AC:

1414

AN:

86166

European-Finnish (FIN)

AF:

0.00824

AC:

408

AN:

49498

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

4186

European-Non Finnish (NFE)

AF:

0.0123

AC:

13630

AN:

1111678

Other (OTH)

AF:

0.0112

AC:

676

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

991

1982

2973

3964

4955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.00845

AC:

1287

AN:

152286

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

617

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41560

American (AMR)

AF:

0.00960

AC:

147

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0128

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00716

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

836

AN:

68022

Other (OTH)

AF:

0.0138

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

200

266

333

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:

0.0100

Hom.:

Bravo

AF:

0.00775

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0137

EpiControl

AF:

0.0110

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.3

(source)

DANN

Benign

0.35

PhyloP100

-0.76

PromoterAI

-0.00090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.0020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_003502.4:c.2186+7C>T

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over