15-60382402-A-G

Variant names:

• chr15-60382402-A-G
• rs1263497771
• NM_004039.3:c.88T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004039.3(ANXA2):​c.88T>C​(p.Tyr30His) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANXA2 NM_004039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17700168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA2	NM_004039.3	c.88T>C	p.Tyr30His	missense_variant	Exon 3 of 13	ENST00000451270.7	NP_004030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA2	ENST00000451270.7	c.88T>C	p.Tyr30His	missense_variant	Exon 3 of 13	1	NM_004039.3	ENSP00000387545.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142T>C (p.Y48H) alteration is located in exon 3 (coding exon 3) of the ANXA2 gene. This alteration results from a T to C substitution at nucleotide position 142, causing the tyrosine (Y) at amino acid position 48 to be replaced by a histidine (H). 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	Benign	0.22
BayesDel_addAF	Benign	0.00061	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;T;.;.;T;T;T;T;T;.;T;T;T;T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0073
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.74	.;.;T;T;T;T;.;.;T;T;T;T;.;T;T;T;T;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D
REVEL	Benign	0.11
Sift	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.47	T;T;T;T;.;.;T;T;T;.;.;.;T;T;.;.;T;.;.
Polyphen		0.0020	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.58
MutPred		0.38		Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);.;Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);.;Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);Loss of phosphorylation at Y30 (P = 0.0231);
MVP		0.28
MPC		0.19
ClinPred		0.49	T
GERP RS		5.7
Varity_R		0.31
gMVP		0.53

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: rs1263497771; hg19: chr15-60674601;