rs1396799

Variant names:

• chr2-69660751-G-A
• rs1396799
• NM_001320698.2:c.-145+7469G>A

Variant summary

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

The NM_001320698.2(ANXA4):​c.-145+7469G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 151,632 control chromosomes in the GnomAD database, including 1,117 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 0.071 (1117 hom., cov: 31)
• Consequence: ANXA4 NM_001320698.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 1 publications found

Genes affected

ANXA4 (HGNC:542): (annexin A4) Annexin IV (ANX4) belongs to the annexin family of calcium-dependent phospholipid binding proteins. Although their functions are still not clearly defined, several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. ANX4 has 45 to 59% identity with other members of its family and shares a similar size and exon-intron organization. Isolated from human placenta, ANX4 encodes a protein that has possible interactions with ATP, and has in vitro anticoagulant activity and also inhibits phospholipase A2 activity. ANX4 is almost exclusively expressed in epithelial cells. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2016]

AAK1 (HGNC:19679): (AP2 associated kinase 1) This gene encodes a member of the SNF1 subfamily of serine/threonine protein kinases. Adaptor-related protein complex 2 (AP-2 complexes) functions during receptor-mediated endocytosis to trigger clathrin assembly, interact with membrane-bound receptors, and recruit encodytic accessory factors. The encoded protein interacts with and phosphorylates a subunit of the AP-2 complex, which promotes binding of AP-2 to sorting signals found in membrane-bound receptors and subsequent receptor endocytosis. Its kinase activity is stimulated by clathrin. This kinase has been shown to play an important role in regulating the clathrin-mediated endocytosis of the rabies virus, facilitating infection. Inhibitors of this kinase are being studied as candidate therapeutics to disrupt the entry of viruses, including SARS-CoV-2, into target cells. It is also involved in positive regulation of Notch pathway signaling in mammals. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320698.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA4	NM_001320698.2		c.-145+7469G>A		intron	N/A	NP_001307627.1	P09525-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA4	ENST00000892545.1		c.-268+7469G>A		intron	N/A	ENSP00000562604.1
	ANXA4	ENST00000892547.1		c.-47+7469G>A		intron	N/A	ENSP00000562606.1
	ANXA4	ENST00000892549.1		c.-145+7469G>A		intron	N/A	ENSP00000562608.1

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10685 AN: 151514 Hom.: 1115 Cov.: 31

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0361

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0635

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.0668

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

GnomAD4 genome AF: 0.0705 AC: 10697 AN: 151632 Hom.: 1117 Cov.: 31 AF XY: 0.0785 AC XY: 5814 AN XY: 74072

African (AFR) AF: 0.0762 AC: 3152 AN: 41354

American (AMR) AF: 0.223 AC: 3383 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 125 AN: 3464

East Asian (EAS) AF: 0.369 AC: 1892 AN: 5134

South Asian (SAS) AF: 0.173 AC: 827 AN: 4778

European-Finnish (FIN) AF: 0.0635 AC: 667 AN: 10500

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00746 AC: 507 AN: 67932

Other (OTH) AF: 0.0666 AC: 140 AN: 2102

Alfa AF: 0.0400 Hom.: 64

Bravo AF: 0.0869

Asia WGS AF: 0.247 AC: 855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.30
PhyloP100		0.25

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1396799; hg19: chr2-69887883;