15-60361006-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004039.3(ANXA2):c.292G>T(p.Val98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,228 control chromosomes in the GnomAD database, including 12,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.086 (733 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11370 hom.)
• Consequence: ANXA2 NM_004039.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.38

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002002865).
• BP6: Variant 15-60361006-C-A is Benign according to our data. Variant chr15-60361006-C-A is described in ClinVar as [Benign]. Clinvar id is 1238049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA2	NM_004039.3	c.292G>T	p.Val98Leu	missense_variant	5/13	ENST00000451270.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA2	ENST00000451270.7	c.292G>T	p.Val98Leu	missense_variant	5/13	1	NM_004039.3	P1

Frequencies

GnomAD3 genomes AF: 0.0857 AC: 13041 AN: 152148 Hom.: 733 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0797

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0855

GnomAD3 exomes AF: 0.0919 AC: 23107 AN: 251394 Hom.: 1405 AF XY: 0.0948 AC XY: 12875 AN XY: 135862

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0488

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.119 AC: 173316 AN: 1460962 Hom.: 11370 Cov.: 30 AF XY: 0.117 AC XY: 84766 AN XY: 726842

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0515

Gnomad4 FIN exome AF: 0.0967

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.0856 AC: 13036 AN: 152266 Hom.: 733 Cov.: 33 AF XY: 0.0827 AC XY: 6156 AN XY: 74458

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0796

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0487

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.0846

Alfa AF: 0.113 Hom.: 514

Bravo AF: 0.0818

TwinsUK AF: 0.134 AC: 497

ALSPAC AF: 0.126 AC: 485

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.133 AC: 1144

ExAC AF: 0.0936 AC: 11367

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.138

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2021

This variant is associated with the following publications: (PMID: 28456096) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.095	T;T;.;T;.;T;.;T;T;T;T;T;.;T;T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.00049	P;P;P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;.;T;.;T;T;T;.;.;.;T;T;.;.
Polyphen		0.0	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.15
MutPred		0.24		Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);.;Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);.;Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);Gain of disorder (P = 0.0627);.;Gain of disorder (P = 0.0627);
MPC		0.13
ClinPred		0.0081	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.49

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: rs17845226; hg19: chr15-60653205; COSMIC: COSV60316858; COSMIC: COSV60316858;