rs2306416

Positions:

• chr4-121696533-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001154.4(ANXA5):​c.9+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,333,308 control chromosomes in the GnomAD database, including 15,025 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2512 hom., cov: 33)
  • Exomes 𝑓: 0.14 (12513 hom.)
• Consequence: ANXA5 NM_001154.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANXA5	NM_001154.4	c.9+48A>G		intron_variant		ENST00000296511.10	NP_001145.1
ANXA5	XM_017008141.3	c.9+48A>G		intron_variant			XP_016863630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANXA5	ENST00000296511.10	c.9+48A>G		intron_variant		1	NM_001154.4	ENSP00000296511	P1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26750 AN: 152102 Hom.: 2505 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.132 AC: 16417 AN: 124724 Hom.: 1123 AF XY: 0.129 AC XY: 8637 AN XY: 67184

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0819

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.141 AC: 166357 AN: 1181088 Hom.: 12513 Cov.: 29 AF XY: 0.140 AC XY: 80104 AN XY: 571864

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.176 AC: 26785 AN: 152220 Hom.: 2512 Cov.: 33 AF XY: 0.174 AC XY: 12962 AN XY: 74440

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.172

Alfa AF: 0.147 Hom.: 3583

Bravo AF: 0.184

Asia WGS AF: 0.194 AC: 673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2306416; hg19: chr4-122617688; COSMIC: COSV56639576;