Genetic Variant ACAP3:p.Arg798Leu (chr1-1293676-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030649.3(ACAP3):c.2393G>T(p.Arg798Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 145,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACAP3
NM_030649.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

Variant links:

Genes affected

ACAP3 (HGNC:16754): (ArfGAP with coiled-coil, ankyrin repeat and PH domains 3) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within neuron migration and regulation of neuron projection development. Predicted to be located in growth cone. [provided by Alliance of Genome Resources, Apr 2022]

ACAP3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAP3	NM_030649.3 link	c.2393G>T	p.Arg798Leu	missense_variant	Exon 24 of 24	ENST00000354700.10	NP_085152.2	Q96P50-3Q8WTZ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACAP3	ENST00000354700.10 link	c.2393G>T	p.Arg798Leu	missense_variant	Exon 24 of 24	1	NM_030649.3	ENSP00000346733.5	Q96P50-3
ACAP3	ENST00000353662.4 link	c.2168G>T	p.Arg723Leu	missense_variant	Exon 21 of 21	1		ENSP00000321139.4	Q96P50-1
ACAP3	ENST00000467278.5 link	n.1919G>T		non_coding_transcript_exon_variant	Exon 14 of 14	1
ACAP3	ENST00000492936.5 link	n.4033G>T		non_coding_transcript_exon_variant	Exon 22 of 22	1

Frequencies

GnomAD3 genomes

AF:

0.00000687

AC:

AN:

145654

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1307944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

645184

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000687

AC:

AN:

145654

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

71036

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2393G>T (p.R798L) alteration is located in exon 24 (coding exon 24) of the ACAP3 gene. This alteration results from a G to T substitution at nucleotide position 2393, causing the arginine (R) at amino acid position 798 to be replaced by a leucine (L). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.20

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.68

P;D

Vest4

0.36

MutPred

0.44

Loss of disorder (P = 0.0753);.;

MVP

0.58

MPC

0.82

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.84

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

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