Variant 7-151119988-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_031946.7(AGAP3):c.971C>T(p.Ala324Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

AGAP3
NM_031946.7 missense, splice_region

Scores

Splicing: ADA: 0.3881

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity AGAP3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14394182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGAP3	NM_031946.7 linkuse as main transcript	c.971C>T	p.Ala324Val	missense_variant, splice_region_variant	8/18	ENST00000397238.7	NP_114152.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGAP3	ENST00000397238.7 linkuse as main transcript	c.971C>T	p.Ala324Val	missense_variant, splice_region_variant	8/18	1	NM_031946.7	ENSP00000380413	P1	Q96P47-4

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000974

AC:

AN:

246454

Hom.:

AF XY:

0.0000969

AC XY:

AN XY:

134160

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

314

AN:

1461296

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000263

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000112

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.0000662

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.971C>T (p.A324V) alteration is located in exon 8 (coding exon 8) of the AGAP3 gene. This alteration results from a C to T substitution at nucleotide position 971, causing the alanine (A) at amino acid position 324 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

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

.;.;.;T;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.2

N;N;N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.059

T;D;D;.;D;D

Sift4G

Benign

0.093

T;T;T;T;D;T

Polyphen

0.035, 0.059

.;.;B;.;B;.

Vest4

0.69

MVP

0.52

MPC

0.49

ClinPred

0.094

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.39

dbscSNV1_RF

Benign

0.68

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