Genetic Variant AGAP3:p.Ile316Val (chr7-151118609-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031946.7(AGAP3):c.946A>G(p.Ile316Val) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,613,514 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

AGAP3
NM_031946.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Variant links:

Genes affected

AGAP3 (HGNC:16923): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 3) This gene encodes an essential component of the N-methyl-D-aspartate (NMDA) receptor signaling complex which mediates long-term potentiation in synapses by linking activation of NMDA receptor to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking. The encoded protein contains an N-terminal GTPase-like domain, a pleckstrin homology domain, an ArfGAP domain and several C-terminal ankryn repeat domains. [provided by RefSeq, Apr 2017]

AGAP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025805682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP3	NM_031946.7 link	c.946A>G	p.Ile316Val	missense_variant	Exon 7 of 18	ENST00000397238.7	NP_114152.3	Q96P47-4Q86XV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP3	ENST00000397238.7 link	c.946A>G	p.Ile316Val	missense_variant	Exon 7 of 18	1	NM_031946.7	ENSP00000380413.2		Q96P47-4

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000366

AC:

AN:

248440

Hom.:

AF XY:

0.000489

AC XY:

AN XY:

134974

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000802

Gnomad NFE exome

AF:

0.000603

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.000262

AC:

383

AN:

1461376

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00113

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000217

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000269

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.946A>G (p.I316V) alteration is located in exon 7 (coding exon 7) of the AGAP3 gene. This alteration results from a A to G substitution at nucleotide position 946, causing the isoleucine (I) at amino acid position 316 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Benign

0.31

DEOGEN2

Benign

0.024

.;.;.;.;T;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.026

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.60

.;.;.;.;N;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.31

N;N;N;N;.;N;N

REVEL

Benign

0.046

Sift

Benign

1.0

T;T;T;T;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Polyphen

0.0040, 0.098, 0.013

.;.;B;B;.;B;.

Vest4

0.37

MVP

0.36

MPC

0.39

ClinPred

0.019

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over