Genetic Variant ANXA5:p.Tyr257Tyr (chr4-121669963-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001154.4(ANXA5):c.771T>C(p.Tyr257Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,601,992 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 8 hom. )

Consequence

ANXA5
NM_001154.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.44

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 4-121669963-A-G is Benign according to our data. Variant chr4-121669963-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 712995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.44 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 8 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA5	NM_001154.4 link	c.771T>C	p.Tyr257Tyr	synonymous_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.771T>C	p.Tyr257Tyr	synonymous_variant	Exon 11 of 13	1	NM_001154.4	ENSP00000296511.5		P08758

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00130

AC:

318

AN:

244426

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000436

Gnomad AMR exome

AF:

0.000428

Gnomad ASJ exome

AF:

0.00162

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00250

AC:

3619

AN:

1449642

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1761

AN XY:

721510

show subpopulations

African (AFR)

AF:

0.000305

AC:

AN:

32820

American (AMR)

AF:

0.000494

AC:

AN:

42512

Ashkenazi Jewish (ASJ)

AF:

0.00128

AC:

AN:

25878

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.000344

AC:

AN:

84286

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00306

AC:

3381

AN:

1105456

Other (OTH)

AF:

0.00225

AC:

135

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

157

314

471

628

785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152350

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000721

AC:

AN:

41590

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00251

AC:

171

AN:

68032

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00173

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00261

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.0

(source)

DANN

Benign

0.56

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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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4-121669963-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over