chr15-60364485-G-C

Variant names:

• chr15-60364485-G-C
• rs11553794
• NM_004039.3:c.187C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004039.3(ANXA2):​c.187C>G​(p.Arg63Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANXA2 NM_004039.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA2	NM_004039.3	c.187C>G	p.Arg63Gly	missense_variant	Exon 4 of 13	ENST00000451270.7	NP_004030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA2	ENST00000451270.7	c.187C>G	p.Arg63Gly	missense_variant	Exon 4 of 13	1	NM_004039.3	ENSP00000387545.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250202 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460902 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.;T;.;.;T;T;T;T;T;.;T;T;T;T;T;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;.;.;D;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;.;.;D;D;D;.;.;.;D;D;.;.;D;.
Polyphen		1.0	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.79		Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);.;Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);.;Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);
MVP		0.53
MPC		0.50
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.92

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: rs11553794; hg19: chr15-60656684;