Genetic Variant AGAP1:p.Ala52Thr (chr2-235494840-G-A) – 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.154G>A(p.Ala52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A52S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

AGAP1
NM_001037131.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.86

Publications

1 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:

Genome browser will be placed here

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=0.25977728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037131.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGAP1	NM_001037131.3	MANE Select	c.154G>A	p.Ala52Thr	missense	Exon 1 of 18	NP_001032208.1	Q9UPQ3-1
AGAP1	NM_014914.5		c.154G>A	p.Ala52Thr	missense	Exon 1 of 17	NP_055729.2	Q9UPQ3-2
AGAP1	NM_001244888.2		c.154G>A	p.Ala52Thr	missense	Exon 1 of 10	NP_001231817.1	Q9UPQ3-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGAP1	ENST00000304032.13	TSL:5 MANE Select	c.154G>A	p.Ala52Thr	missense	Exon 1 of 18	ENSP00000307634.7	Q9UPQ3-1
AGAP1	ENST00000336665.9	TSL:1	c.154G>A	p.Ala52Thr	missense	Exon 1 of 17	ENSP00000338378.5	Q9UPQ3-2
AGAP1	ENST00000409457.5	TSL:1	c.154G>A	p.Ala52Thr	missense	Exon 1 of 10	ENSP00000387174.1	Q9UPQ3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

216422

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418086

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705456

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29572

American (AMR)

AF:

0.00

AC:

AN:

40154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24626

East Asian (EAS)

AF:

0.00

AC:

AN:

34514

South Asian (SAS)

AF:

0.00

AC:

AN:

82734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090044

Other (OTH)

AF:

0.00

AC:

AN:

58264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.4

PhyloP100

1.9

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.091

Sift4G

Benign

0.25

Polyphen

0.17

Vest4

0.26

MutPred

0.20

Gain of helix (P = 0.132)

MVP

0.76

MPC

0.44

ClinPred

0.47

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.29

Mutation Taster

=70/30

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over