4-121669669-A-G

Position:

• chr4-121669669-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001154.4(ANXA5):​c.836T>C​(p.Ile279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,613,360 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (15 hom.)
• Consequence: ANXA5 NM_001154.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.82

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016770035).
• BP6: Variant 4-121669669-A-G is Benign according to our data. Variant chr4-121669669-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3049443.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA5	NM_001154.4	c.836T>C	p.Ile279Thr	missense_variant	12/13	ENST00000296511.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA5	ENST00000296511.10	c.836T>C	p.Ile279Thr	missense_variant	12/13	1	NM_001154.4	P1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 183 AN: 151810 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00978

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000963

GnomAD3 exomes AF: 0.00238 AC: 597 AN: 250952 Hom.: 5 AF XY: 0.00285 AC XY: 386 AN XY: 135624

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00996

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00157 AC: 2295 AN: 1461434 Hom.: 15 Cov.: 30 AF XY: 0.00184 AC XY: 1341 AN XY: 727014

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000962

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00120 AC: 183 AN: 151926 Hom.: 4 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74236

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000657

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00979

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000953

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00264 AC: 320

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANXA5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.066
Sift	Benign	0.058	T;D;T
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.20	B;B;P
Vest4		0.58
MVP		0.62
MPC		0.24
ClinPred		0.033	T
GERP RS		3.4
Varity_R		0.35
gMVP		0.57

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: rs17851665; hg19: chr4-122590824;