rs1396798

Variant names:

• chr2-69660705-G-T
• rs1396798
• NM_001320698.2:c.-145+7423G>T

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+7423G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 151,454 control chromosomes in the GnomAD database, including 6,641 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 0.29 (6641 hom., cov: 31)
• Consequence: ANXA4 NM_001320698.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 3 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANXA4	NM_001320698.2	c.-145+7423G>T		intron_variant	Intron 2 of 14		NP_001307627.1
ANXA4	XM_017003943.2	c.-302+7423G>T		intron_variant	Intron 2 of 15		XP_016859432.1
ANXA4	XM_024452835.2	c.-2827+7423G>T		intron_variant	Intron 2 of 15		XP_024308603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANXA4	ENST00000418066.2	n.766+7423G>T		intron_variant	Intron 2 of 3	3
AAK1	ENST00000461002.1	n.327+13318C>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44050 AN: 151336 Hom.: 6627 Cov.: 31

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.304

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

GnomAD4 genome AF: 0.291 AC: 44096 AN: 151454 Hom.: 6641 Cov.: 31 AF XY: 0.291 AC XY: 21535 AN XY: 73954

African (AFR) AF: 0.337 AC: 13931 AN: 41280

American (AMR) AF: 0.279 AC: 4236 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 889 AN: 3452

East Asian (EAS) AF: 0.394 AC: 2026 AN: 5148

South Asian (SAS) AF: 0.324 AC: 1557 AN: 4802

European-Finnish (FIN) AF: 0.206 AC: 2155 AN: 10438

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.270 AC: 18342 AN: 67844

Other (OTH) AF: 0.301 AC: 634 AN: 2106

Alfa AF: 0.281 Hom.: 2981

Bravo AF: 0.297

Asia WGS AF: 0.328 AC: 1141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.66
PhyloP100		0.25

Splicing

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

Other links and lift over

dbSNP: rs1396798; hg19: chr2-69887837;