Genetic Variant ANXA5:p.Met259Leu (chr4-121669959-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001154.4(ANXA5):c.775A>T(p.Met259Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,252 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M259V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANXA5
NM_001154.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.71

Publications

0 publications found

Variant links:

Genes affected

ANXA5 (HGNC:543): (annexin A5) The Annexin 5 gene spans 29 kb containing 13 exons, and encodes a single transcript of approximately 1.6 kb and a protein product with a molecular weight of about 35 kDa.The protein encoded by this gene belongs to the annexin family of calcium-dependent phospholipid binding proteins some of which have been implicated in membrane-related events along exocytotic and endocytotic pathways. Annexin 5 is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and a potential role in cellular signal transduction, inflammation, growth and differentiation. Annexin 5 has also been described as placental anticoagulant protein I, vascular anticoagulant-alpha, endonexin II, lipocortin V, placental protein 4 and anchorin CII. Polymorphisms in this gene have been implicated in various obstetric complications. [provided by RefSeq, Dec 2019]

ANXA5 Gene-Disease associations (from GenCC):

pregnancy loss, recurrent, susceptibility to, 3
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ANXA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA5	NM_001154.4 link	c.775A>T	p.Met259Leu	missense_variant	Exon 11 of 13	ENST00000296511.10	NP_001145.1	P08758V9HWE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA5	ENST00000296511.10 link	c.775A>T	p.Met259Leu	missense_variant	Exon 11 of 13	1	NM_001154.4	ENSP00000296511.5		P08758

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445252

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32552

American (AMR)

AF:

0.00

AC:

AN:

41382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25728

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

83530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103544

Other (OTH)

AF:

0.00

AC:

AN:

59850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

0.083

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.4

N;N;D

REVEL

Benign

0.16

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.078

T;T;T

Polyphen

0.011

B;B;P

Vest4

0.41

MutPred

0.82

Loss of ubiquitination at K260 (P = 0.0997);.;.;

MVP

0.63

MPC

0.20

ClinPred

0.95

GERP RS

4.3

Varity_R

0.64

gMVP

0.79

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over