8-123684663-C-T

Variant names:

• chr8-123684663-C-T
• rs1813104965
• NM_004306.4:c.778G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004306.4(ANXA13):​c.778G>A​(p.Gly260Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANXA13 NM_004306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

Genes affected

ANXA13 (HGNC:536): (annexin A13) This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. The specific function of this gene has not yet been determined; however, it is associated with the plasma membrane of undifferentiated, proliferating endothelial cells and differentiated villus enterocytes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA13	NM_004306.4	c.778G>A	p.Gly260Ser	missense_variant	Exon 10 of 11	ENST00000419625.6	NP_004297.2
ANXA13	NM_001003954.3	c.901G>A	p.Gly301Ser	missense_variant	Exon 11 of 12		NP_001003954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA13	ENST00000419625.6	c.778G>A	p.Gly260Ser	missense_variant	Exon 10 of 11	1	NM_004306.4	ENSP00000390809.1
ANXA13	ENST00000262219.10	c.901G>A	p.Gly301Ser	missense_variant	Exon 11 of 12	1		ENSP00000262219.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.901G>A (p.G301S) alteration is located in exon 11 (coding exon 11) of the ANXA13 gene. This alteration results from a G to A substitution at nucleotide position 901, causing the glycine (G) at amino acid position 301 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.79		.;Loss of ubiquitination at K259 (P = 0.0603);
MVP		0.77
MPC		0.62
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1813104965; hg19: chr8-124696903;