NM_003502.4:c.2537T>C

Variant names:

• chr16-288174-A-G
• rs2141459394
• NM_003502.4:c.2537T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003502.4(AXIN1):​c.2537T>C​(p.Val846Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AXIN1 NM_003502.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27917796).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	NM_003502.4	MANE Select	c.2537T>C	p.Val846Ala	missense	Exon 11 of 11	NP_003493.1	A0A0S2Z4R0
	AXIN1	NM_181050.3		c.2429T>C	p.Val810Ala	missense	Exon 10 of 10	NP_851393.1	O15169-2
	AXIN1	NR_134879.2		n.2768T>C		non_coding_transcript_exon	Exon 9 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN1	ENST00000262320.8	TSL:1 MANE Select	c.2537T>C	p.Val846Ala	missense	Exon 11 of 11	ENSP00000262320.3	O15169-1
	AXIN1	ENST00000354866.7	TSL:1	c.2429T>C	p.Val810Ala	missense	Exon 10 of 10	ENSP00000346935.3	O15169-2
	AXIN1	ENST00000957925.1		c.2552T>C	p.Val851Ala	missense	Exon 11 of 11	ENSP00000627984.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.061
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.10	T
Polyphen		0.069	B
Vest4		0.086
MutPred		0.51		Loss of stability (P = 0.0312)
MVP		0.49
MPC		0.46
ClinPred		0.50	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.45
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs2141459394; hg19: chr16-338174;