Genetic Variant AGAP9:p.Arg249Leu (chr10-47503383-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001190810.1(AGAP9):c.746G>T(p.Arg249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00079 ( 11 hom., cov: 26)

Exomes 𝑓: 0.00012 ( 13 hom. )

Failed GnomAD Quality Control

Consequence

AGAP9
NM_001190810.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

Variant links:

Genes affected

AGAP9 (HGNC:23463): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 9) 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]

AGAP9 links:

ANXA8 (HGNC:546): (annexin A8) This gene encodes a member of the annexin family of evolutionarily conserved Ca2+ and phospholipid binding proteins. The encoded protein may function as an an anticoagulant that indirectly inhibits the thromboplastin-specific complex. Overexpression of this gene has been associated with acute myelocytic leukemia. A highly similar duplicated copy of this gene is found in close proximity on the long arm of chromosome 10. [provided by RefSeq, Jul 2008]

ANXA8 links:

BMS1P2-AGAP9 (HGNC:):

BMS1P2-AGAP9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30863857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP9	NM_001190810.1 link	c.746G>T	p.Arg249Leu	missense_variant	Exon 8 of 8	ENST00000452145.6	NP_001177739.1	Q5VTM2-2
ANXA8	XM_006717951.4 link	c.94-23495G>T		intron_variant	Intron 1 of 11		XP_006718014.1
BMS1P2-AGAP9	NR_160414.1 link	n.1804G>T		non_coding_transcript_exon_variant	Exon 16 of 16
BMS1P2-AGAP9	NR_160415.1 link	n.2161G>T		non_coding_transcript_exon_variant	Exon 16 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP9	ENST00000452145.6 link	c.746G>T	p.Arg249Leu	missense_variant	Exon 8 of 8	1	NM_001190810.1	ENSP00000392206.2		Q5VTM2-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

115

AN:

148434

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000136

AC:

AN:

73398

Hom.:

AF XY:

0.0000277

AC XY:

AN XY:

36166

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 SAS exome

AF:

0.000159

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000125

AC:

182

AN:

1461280

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00429

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000788

AC:

117

AN:

148542

Hom.:

Cov.:

AF XY:

0.000745

AC XY:

AN XY:

72520

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746G>T (p.R249L) alteration is located in exon 8 (coding exon 8) of the AGAP9 gene. This alteration results from a G to T substitution at nucleotide position 746, causing the arginine (R) at amino acid position 249 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

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.74

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.31

PROVEAN

Pathogenic

-5.1

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Vest4

0.29

MVP

0.57

GERP RS

0.11

gMVP

0.059

Splicing

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