Variant 10-73675323-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000374094.9(AGAP5):c.1337T>C(p.Leu446Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGAP5
ENST00000374094.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.46

Variant links:

Genes affected

AGAP5 (HGNC:23467): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 5) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

AGAP5 links:

SYNPO2L-AS1 (HGNC:55242): (SYNPO2L antisense RNA 1)

SYNPO2L-AS1 links:

BMS1P4-AGAP5 (HGNC:):

BMS1P4-AGAP5 links:

Genome browser will be placed here

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/exons	MANE	Protein
AGAP5	NM_001144000.4 linkuse as main transcript	c.1337T>C	p.Leu446Pro	missense_variant	8/8	ENST00000374094.9	NP_001137472.1
BMS1P4-AGAP5	NR_160426.1 linkuse as main transcript	n.3604T>C		non_coding_transcript_exon_variant	20/20
BMS1P4-AGAP5	NR_160425.1 linkuse as main transcript	n.2816T>C		non_coding_transcript_exon_variant	19/19
BMS1P4-AGAP5	NR_160427.1 linkuse as main transcript	n.2748T>C		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGAP5	ENST00000374094.9 linkuse as main transcript	c.1337T>C	p.Leu446Pro	missense_variant	8/8	1	NM_001144000.4	ENSP00000363207	A2
SYNPO2L-AS1	ENST00000668336.1 linkuse as main transcript	n.1078A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151926

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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

AF:

0.00000342

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000658

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1337T>C (p.L446P) alteration is located in exon 8 (coding exon 8) of the AGAP5 gene. This alteration results from a T to C substitution at nucleotide position 1337, causing the leucine (L) at amino acid position 446 to be replaced by a proline (P). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.40

.;.;T

Eigen

Benign

0.054

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.77

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.0054

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

4.0

.;.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.0

.;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.010

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.67

MutPred

0.44

Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);

MVP

0.21

ClinPred

0.99

Varity_R

0.69

gMVP

0.51

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