Genetic Variant AGAP1:p.Val671Ile (chr2-236049178-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001037131.3(AGAP1):c.2011G>A(p.Val671Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,613,972 control chromosomes in the GnomAD database, including 257,386 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V671V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.65 ( 33870 hom., cov: 33)

Exomes 𝑓: 0.55 ( 223516 hom. )

Consequence

AGAP1
NM_001037131.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.932896E-7).

BP6

Variant 2-236049178-G-A is Benign according to our data. Variant chr2-236049178-G-A is described in ClinVar as [Benign]. Clinvar id is 2114466.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP1	NM_001037131.3 link	c.2011G>A	p.Val671Ile	missense_variant	Exon 16 of 18	ENST00000304032.13	NP_001032208.1	Q9UPQ3-1B2RZG9
AGAP1	NM_001436125.1 link	c.2806G>A	p.Val936Ile	missense_variant	Exon 16 of 18		NP_001423054.1
AGAP1	NM_001436126.1 link	c.2647G>A	p.Val883Ile	missense_variant	Exon 15 of 17		NP_001423055.1
AGAP1	NM_014914.5 link	c.1852G>A	p.Val618Ile	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>A	p.Val671Ile	missense_variant	Exon 16 of 18	5	NM_001037131.3	ENSP00000307634.7		Q9UPQ3-1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98504

AN:

152022

Hom.:

33807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.877

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.677

Gnomad ASJ

AF:

0.456

Gnomad EAS

AF:

0.746

Gnomad SAS

AF:

0.539

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.614

GnomAD2 exomes

AF:

0.604

AC:

151849

AN:

251470

AF XY:

0.586

show subpopulations

Gnomad AFR exome

AF:

0.884

Gnomad AMR exome

AF:

0.774

Gnomad ASJ exome

AF:

0.442

Gnomad EAS exome

AF:

0.749

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.529

Gnomad OTH exome

AF:

0.573

GnomAD4 exome

AF:

0.547

AC:

798974

AN:

1461830

Hom.:

223516

Cov.:

AF XY:

0.544

AC XY:

395968

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.886

AC:

29662

AN:

33478

American (AMR)

AF:

0.763

AC:

34136

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

11414

AN:

26136

East Asian (EAS)

AF:

0.749

AC:

29734

AN:

39698

South Asian (SAS)

AF:

0.541

AC:

46642

AN:

86258

European-Finnish (FIN)

AF:

0.557

AC:

29770

AN:

53418

Middle Eastern (MID)

AF:

0.525

AC:

3028

AN:

5768

European-Non Finnish (NFE)

AF:

0.522

AC:

580863

AN:

1111956

Other (OTH)

AF:

0.558

AC:

33725

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

20146

40293

60439

80586

100732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16806

33612

50418

67224

84030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.648

AC:

98623

AN:

152142

Hom.:

33870

Cov.:

AF XY:

0.648

AC XY:

48172

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.877

AC:

36402

AN:

41512

American (AMR)

AF:

0.678

AC:

10363

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.456

AC:

1584

AN:

3470

East Asian (EAS)

AF:

0.746

AC:

3859

AN:

5170

South Asian (SAS)

AF:

0.537

AC:

2591

AN:

4824

European-Finnish (FIN)

AF:

0.568

AC:

6009

AN:

10570

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.530

AC:

36043

AN:

67996

Other (OTH)

AF:

0.611

AC:

1288

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1622

3244

4866

6488

8110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.557

Hom.:

63439

Bravo

AF:

0.666

TwinsUK

AF:

0.516

AC:

1912

ALSPAC

AF:

0.528

AC:

2036

ESP6500AA

AF:

0.863

AC:

3804

ESP6500EA

AF:

0.516

AC:

4439

ExAC

AF:

0.602

AC:

73073

Asia WGS

AF:

0.638

AC:

2217

AN:

3478

EpiCase

AF:

0.518

EpiControl

AF:

0.516

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.055

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.031

.;T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.19

T;T;T;T;T

MetaRNN

Benign

6.9e-7

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.;.;.

PhyloP100

0.64

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.27

N;N;N;.;.

REVEL

Benign

0.035

Sift

Benign

0.42

T;T;T;.;.

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.088

MPC

0.33

ClinPred

0.0030

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.089

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over