rs75993598

Positions:

• chr15-60382363-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004039.3(ANXA2):​c.127G>A​(p.Glu43Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANXA2 NM_004039.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53

Genes affected

ANXA2 (HGNC:537): (annexin A2) 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. This protein functions as an autocrine factor which heightens osteoclast formation and bone resorption. This gene has three pseudogenes located on chromosomes 4, 9 and 10, respectively. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. Annexin A2 expression has been found to correlate with resistance to treatment against various cancer forms. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA2	NM_004039.3	c.127G>A	p.Glu43Lys	missense_variant	3/13	ENST00000451270.7	NP_004030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA2	ENST00000451270.7	c.127G>A	p.Glu43Lys	missense_variant	3/13	1	NM_004039.3	ENSP00000387545	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;T;.;T;.;.;T;T;T;T;T;.;T;T;T;T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	.;.;D;D;D;D;.;.;D;D;T;T;.;D;D;D;T;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D
REVEL	Benign	0.23
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.56	T;T;T;T;.;.;T;T;T;.;.;.;T;T;.;.;T;.;.
Polyphen		0.99	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.78
MutPred		0.59		Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);.;Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);.;Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);Loss of stability (P = 0.0522);
MVP		0.51
MPC		0.47
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs75993598; hg19: chr15-60674562;