16-289494-C-G

Variant names:

• chr16-289494-C-G
• rs144411078
• NM_003502.4:c.2408G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003502.4(AXIN1):​c.2408G>C​(p.Arg803Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R803H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AXIN1 NM_003502.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN1	NM_003502.4	c.2408G>C	p.Arg803Pro	missense_variant	Exon 10 of 11	ENST00000262320.8	NP_003493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN1	ENST00000262320.8	c.2408G>C	p.Arg803Pro	missense_variant	Exon 10 of 11	1	NM_003502.4	ENSP00000262320.3
AXIN1	ENST00000354866.7	c.2300G>C	p.Arg767Pro	missense_variant	Exon 9 of 10	1		ENSP00000346935.3
AXIN1	ENST00000457798.1	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 3	3		ENSP00000416835.1
AXIN1	ENST00000461023.5	n.5477G>C		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		4.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.35
Sift	Benign	0.20	T;T
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.68		Loss of catalytic residue at R803 (P = 0.0318);.;
MVP		0.53
MPC		1.3
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.82
Mutation Taster		=36/64	disease causing

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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Other links and lift over

dbSNP: rs144411078; hg19: chr16-339494;