4-121690130-G-A

Variant names:

• chr4-121690130-G-A
• rs6857766
• NM_001154.4:c.10-3758C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001154.4(ANXA5):​c.10-3758C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,122 control chromosomes in the GnomAD database, including 4,168 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 0.23 (4168 hom., cov: 32)
• Consequence: ANXA5 NM_001154.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.918
• Publications: 24 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001154.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA5	NM_001154.4	MANE Select	c.10-3758C>T		intron	N/A	NP_001145.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA5	ENST00000296511.10	TSL:1 MANE Select	c.10-3758C>T		intron	N/A	ENSP00000296511.5
	ANXA5	ENST00000501272.6	TSL:5	c.9+6451C>T		intron	N/A	ENSP00000424106.1
	ANXA5	ENST00000515017.5	TSL:5	c.10-3758C>T		intron	N/A	ENSP00000424199.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34280 AN: 152004 Hom.: 4162 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.217

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.226 AC: 34315 AN: 152122 Hom.: 4168 Cov.: 32 AF XY: 0.221 AC XY: 16419 AN XY: 74360

African (AFR) AF: 0.317 AC: 13157 AN: 41480

American (AMR) AF: 0.185 AC: 2829 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3468

East Asian (EAS) AF: 0.149 AC: 770 AN: 5170

South Asian (SAS) AF: 0.173 AC: 835 AN: 4816

European-Finnish (FIN) AF: 0.141 AC: 1492 AN: 10590

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13688 AN: 67982

Other (OTH) AF: 0.215 AC: 455 AN: 2114

Alfa AF: 0.204 Hom.: 14214

Bravo AF: 0.235

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.3
DANN	Benign	0.66
PhyloP100		0.92
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: rs6857766; hg19: chr4-122611285;