12-57726710-C-A

Variant names:

• chr12-57726710-C-A
• rs1033908207
• NM_001122772.3:c.3421G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001122772.3(AGAP2):​c.3421G>T​(p.Asp1141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000544 in 1,103,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1141H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: AGAP2 NM_001122772.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

AGAP2 (HGNC:16921): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2) The protein encoded by this gene belongs to the centaurin gamma-like family. It mediates anti-apoptotic effects of nerve growth factor by activating nuclear phosphoinositide 3-kinase. It is overexpressed in cancer cells, and promotes cancer cell invasion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

AGAP2-AS1 (HGNC:48633): (AGAP2 antisense RNA 1) Biomarker of lung non-small cell carcinoma; malignant astrocytoma; and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

OS9 (HGNC:16994): (OS9 endoplasmic reticulum lectin) This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3	c.3421G>T	p.Asp1141Tyr	missense_variant	Exon 19 of 19	ENST00000547588.6	NP_001116244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000547588.6	c.3421G>T	p.Asp1141Tyr	missense_variant	Exon 19 of 19	1	NM_001122772.3	ENSP00000449241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000544 AC: 6 AN: 1103868 Hom.: 0 Cov.: 32 AF XY: 0.00000570 AC XY: 3 AN XY: 525914

African (AFR) AF: 0.00 AC: 0 AN: 22056

American (AMR) AF: 0.00 AC: 0 AN: 7932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13814

East Asian (EAS) AF: 0.00 AC: 0 AN: 23786

South Asian (SAS) AF: 0.000158 AC: 5 AN: 31564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 932276

Other (OTH) AF: 0.00 AC: 0 AN: 43862

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.46	T
PhyloP100		4.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.49		.;Loss of disorder (P = 0.0568);
MVP		0.70
MPC		2.7
ClinPred		1.0	D
GERP RS		3.2
gMVP		0.69
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1033908207; hg19: chr12-58120493;