Genetic Variant AGAP1:p.Val671Leu (chr2-236049178-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001037131.3(AGAP1):c.2011G>C(p.Val671Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. V671I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

AGAP1
NM_001037131.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.638

Publications

35 publications found

Variant links:

Genes affected

AGAP1 (HGNC:16922): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 1) This gene encodes a member of an ADP-ribosylation factor GTPase-activating protein family involved in membrane trafficking and cytoskeleton dynamics. This gene functions as a direct regulator of the adaptor-related protein complex 3 on endosomes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

AGAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042730957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP1	NM_001037131.3 link	c.2011G>C	p.Val671Leu	missense_variant	Exon 16 of 18	ENST00000304032.13	NP_001032208.1	Q9UPQ3-1B2RZG9
AGAP1	NM_001436125.1 link	c.2806G>C	p.Val936Leu	missense_variant	Exon 16 of 18		NP_001423054.1
AGAP1	NM_001436126.1 link	c.2647G>C	p.Val883Leu	missense_variant	Exon 15 of 17		NP_001423055.1
AGAP1	NM_014914.5 link	c.1852G>C	p.Val618Leu	missense_variant	Exon 15 of 17		NP_055729.2	Q9UPQ3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP1	ENST00000304032.13 link	c.2011G>C	p.Val671Leu	missense_variant	Exon 16 of 18	5	NM_001037131.3	ENSP00000307634.7		Q9UPQ3-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152072

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74272

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.1

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.034

.;T;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.52

T;T;T;T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.043

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

.;N;.;.;.

PhyloP100

0.64

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.74

N;N;N;.;.

REVEL

Benign

0.054

Sift

Benign

0.68

T;T;T;.;.

Sift4G

Benign

0.93

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.060

MutPred

0.55

.;Loss of helix (P = 0.0093);.;.;.;

MVP

0.29

MPC

0.40

ClinPred

0.037

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.20

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over