Genetic Variant AGAP2:p.Thr1158Met (chr12-57726658-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001122772.3(AGAP2):c.3473C>T(p.Thr1158Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000949 in 1,053,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. T1158R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 9.5e-7 ( 0 hom. )

Consequence

AGAP2
NM_001122772.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.83

Publications

0 publications found

Variant links:

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 links:

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]

AGAP2-AS1 links:

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]

OS9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33442274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3 link	c.3473C>T	p.Thr1158Met	missense_variant	Exon 19 of 19	ENST00000547588.6	NP_001116244.1	Q99490F8VVT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000547588.6 link	c.3473C>T	p.Thr1158Met	missense_variant	Exon 19 of 19	1	NM_001122772.3	ENSP00000449241.1		F8VVT9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.49e-7

AC:

AN:

1053420

Hom.:

Cov.:

AF XY:

0.00000201

AC XY:

AN XY:

498622

show subpopulations

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

African (AFR)

AF:

0.0000468

AC:

AN:

21362

American (AMR)

AF:

0.00

AC:

AN:

7042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12430

East Asian (EAS)

AF:

0.00

AC:

AN:

22252

South Asian (SAS)

AF:

0.00

AC:

AN:

22148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3088

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

902340

Other (OTH)

AF:

0.00

AC:

AN:

41226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.73

PhyloP100

3.8

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.99

D;D

Vest4

0.24

MutPred

0.21

.;Loss of glycosylation at T1158 (P = 9e-04);

MVP

0.28

MPC

2.6

ClinPred

0.72

GERP RS

2.5

gMVP

0.28

Mutation Taster

=69/31

polymorphism

(source)

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

Publications

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12-57726658-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over