rs2306416

Variant names:

• chr4-121696533-T-C
• rs2306416
• NM_001154.4:c.9+48A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ANXA5	NM_001154.4	c.9+48A>G		intron_variant	Intron 2 of 12	ENST00000296511.10	NP_001145.1
ANXA5	XM_017008141.3	c.9+48A>G		intron_variant	Intron 2 of 6		XP_016863630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA5	ENST00000296511.10	c.9+48A>G		intron_variant	Intron 2 of 12	1	NM_001154.4	ENSP00000296511.5

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

GnomAD2 exomes AF: 0.132 AC: 16417 AN: 124724 AF XY: 0.129

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.251 AC: 6232 AN: 24804

American (AMR) AF: 0.128 AC: 2393 AN: 18688

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 1817 AN: 16246

East Asian (EAS) AF: 0.144 AC: 4488 AN: 31082

South Asian (SAS) AF: 0.136 AC: 4757 AN: 34984

European-Finnish (FIN) AF: 0.102 AC: 4332 AN: 42642

Middle Eastern (MID) AF: 0.125 AC: 591 AN: 4724

European-Non Finnish (NFE) AF: 0.140 AC: 134494 AN: 960672

Other (OTH) AF: 0.154 AC: 7253 AN: 47246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.254 AC: 10536 AN: 41534

American (AMR) AF: 0.147 AC: 2247 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 449 AN: 3468

East Asian (EAS) AF: 0.192 AC: 992 AN: 5166

South Asian (SAS) AF: 0.167 AC: 807 AN: 4820

European-Finnish (FIN) AF: 0.105 AC: 1114 AN: 10606

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10087 AN: 68000

Other (OTH) AF: 0.172 AC: 363 AN: 2114

Alfa AF: 0.152 Hom.: 7983

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
PhyloP100		-2.3
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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