Genetic Variant AGAP9:p.Met248Val (chr10-47503387-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001190810.1(AGAP9):c.742A>G(p.Met248Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000945 in 148,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000095 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGAP9
NM_001190810.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.91

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00929603).

BP6

Variant 10-47503387-T-C is Benign according to our data. Variant chr10-47503387-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2640436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP9	NM_001190810.1 link	c.742A>G	p.Met248Val	missense_variant	Exon 8 of 8	ENST00000452145.6	NP_001177739.1	Q5VTM2-2
ANXA8	XM_006717951.4 link	c.94-23499A>G		intron_variant	Intron 1 of 11		XP_006718014.1
BMS1P2-AGAP9	NR_160414.1 link	n.1800A>G		non_coding_transcript_exon_variant	Exon 16 of 16
BMS1P2-AGAP9	NR_160415.1 link	n.2157A>G		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.742A>G	p.Met248Val	missense_variant	Exon 8 of 8	1	NM_001190810.1	ENSP00000392206.2		Q5VTM2-2

Frequencies

GnomAD3 genomes

AF:

0.0000946

AC:

AN:

148022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000587

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000864

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000444

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00189

AC:

143

AN:

75508

Hom.:

AF XY:

0.00184

AC XY:

AN XY:

37012

show subpopulations

Gnomad AFR exome

AF:

0.00919

Gnomad AMR exome

AF:

0.000716

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.000908

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000122

AC:

178

AN:

1456358

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

724194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000604

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.000866

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000680

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000712

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000945

AC:

AN:

148130

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

72274

show subpopulations

Gnomad4 AFR

AF:

0.000128

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000587

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000865

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000444

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000429

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGAP9: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.60

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0093

PROVEAN

Benign

-1.2

Sift

Benign

0.13

Sift4G

Benign

0.24

Vest4

0.086

MVP

0.35

GERP RS

0.11

gMVP

0.022

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