Genetic Variant AXIN1:c.2294+111C>A (chr16-291079-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003502.4(AXIN1):c.2294+111C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000235 in 852,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

AXIN1
NM_003502.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.21

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

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	UniProt
AXIN1	NM_003502.4	MANE Select	c.2294+111C>A	intron	N/A	NP_003493.1	A0A0S2Z4R0
AXIN1	NM_181050.3		c.2187-1472C>A	intron	N/A	NP_851393.1	O15169-2
AXIN1	NR_134879.2		n.2526-1472C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.2294+111C>A	intron	N/A	ENSP00000262320.3	O15169-1
AXIN1	ENST00000354866.7	TSL:1	c.2187-1472C>A	intron	N/A	ENSP00000346935.3	O15169-2
AXIN1	ENST00000957925.1		c.2309+111C>A	intron	N/A	ENSP00000627984.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000235

AC:

AN:

852466

Hom.:

Cov.:

AF XY:

0.00000454

AC XY:

AN XY:

440166

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21052

American (AMR)

AF:

0.00

AC:

AN:

34896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21730

East Asian (EAS)

AF:

0.00

AC:

AN:

33206

South Asian (SAS)

AF:

0.00

AC:

AN:

67972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3784

European-Non Finnish (NFE)

AF:

0.00000171

AC:

AN:

583328

Other (OTH)

AF:

0.0000250

AC:

AN:

39922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.039

(source)

DANN

Benign

0.54

PhyloP100

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over