10-47503383-C-A

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

2
3
4

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]
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]

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
AGAP9NM_001190810.1 linkc.746G>T p.Arg249Leu missense_variant Exon 8 of 8 ENST00000452145.6 NP_001177739.1 Q5VTM2-2
ANXA8XM_006717951.4 linkc.94-23495G>T intron_variant Intron 1 of 11 XP_006718014.1
BMS1P2-AGAP9NR_160414.1 linkn.1804G>T non_coding_transcript_exon_variant Exon 16 of 16
BMS1P2-AGAP9NR_160415.1 linkn.2161G>T non_coding_transcript_exon_variant Exon 16 of 16

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGAP9ENST00000452145.6 linkc.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.:
10
Cov.:
26
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:
1
AN:
73398
Hom.:
0
AF XY:
0.0000277
AC XY:
1
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.:
13
Cov.:
33
AF XY:
0.0000990
AC XY:
72
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.:
11
Cov.:
26
AF XY:
0.000745
AC XY:
54
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
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
18
DANN
Benign
0.74
FATHMM_MKL
Benign
0.61
D
LIST_S2
Uncertain
0.92
D
MetaRNN
Benign
0.31
T
PROVEAN
Pathogenic
-5.1
D
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
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.

Other links and lift over

dbSNP: rs1270131442; hg19: chr10-48902730; API