Genetic Variant AGAP1:p.Val671Phe (chr2-236049178-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001037131.3(AGAP1):c.2011G>T(p.Val671Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07774562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP1	NM_001037131.3 link	c.2011G>T	p.Val671Phe	missense_variant	Exon 16 of 18	ENST00000304032.13	NP_001032208.1	Q9UPQ3-1B2RZG9
AGAP1	NM_001436125.1 link	c.2806G>T	p.Val936Phe	missense_variant	Exon 16 of 18		NP_001423054.1
AGAP1	NM_001436126.1 link	c.2647G>T	p.Val883Phe	missense_variant	Exon 15 of 17		NP_001423055.1
AGAP1	NM_014914.5 link	c.1852G>T	p.Val618Phe	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>T	p.Val671Phe	missense_variant	Exon 16 of 18	5	NM_001037131.3	ENSP00000307634.7		Q9UPQ3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251470

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

63439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.6

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.074

.;T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.078

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

.;M;.;.;.

PhyloP100

0.64

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.0

N;N;N;.;.

REVEL

Benign

0.084

Sift

Benign

0.70

T;T;T;.;.

Sift4G

Benign

0.69

T;T;T;T;T

Polyphen

0.023

B;B;.;.;.

Vest4

0.29

MutPred

0.60

.;Gain of loop (P = 0.0045);.;.;.;

MVP

0.44

MPC

0.63

ClinPred

0.065

GERP RS

0.32

Varity_R

0.15

gMVP

0.35

Mutation Taster

=91/9

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over