10-49988891-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001077665.3(AGAP6):​c.176G>A​(p.Gly59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AGAP6
NM_001077665.3 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08
Variant links:
Genes affected
AGAP6 (HGNC:23466): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) 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]
TIMM23B-AGAP6 (HGNC:45009): (TIMM23B-AGAP6 readthrough (NMD candidate)) This locus represents naturally-occurring readthrough transcription between the adjacent TIMM23B (translocase of inner mitochondrial membrane 23 homolog B) and AGAP6 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) genes. Readthrough transcripts contain portions of the coding sequence for both genes and are predicted to be candidates for nonsense-mediated decay (NMD). [provided by RefSeq, Sep 2018]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2313473).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGAP6NM_001077665.3 linkc.176G>A p.Gly59Asp missense_variant Exon 1 of 8 ENST00000412531.7 NP_001071133.2 Q5VW22-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGAP6ENST00000412531.7 linkc.176G>A p.Gly59Asp missense_variant Exon 1 of 8 1 NM_001077665.3 ENSP00000500374.1 Q5VW22-2
TIMM23B-AGAP6ENST00000651763.1 linkn.*391G>A non_coding_transcript_exon_variant Exon 10 of 18 ENSP00000502214.1
TIMM23B-AGAP6ENST00000651763.1 linkn.*391G>A 3_prime_UTR_variant Exon 10 of 18 ENSP00000502214.1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1448658
Hom.:
0
Cov.:
77
AF XY:
0.00
AC XY:
0
AN XY:
721048
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.176G>A (p.G59D) alteration is located in exon 1 (coding exon 1) of the AGAP6 gene. This alteration results from a G to A substitution at nucleotide position 176, causing the glycine (G) at amino acid position 59 to be replaced by an aspartic acid (D). 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
Benign
0.13
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0019
T;.
Eigen
Benign
0.072
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.23
T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
1.2
L;L
PrimateAI
Pathogenic
0.91
D
PROVEAN
Benign
-0.14
N;N
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.10
T;T
Vest4
0.28
MutPred
0.16
Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP
0.29
ClinPred
0.84
D
GERP RS
1.2
Varity_R
0.17
gMVP
0.019

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-51748651; API