10-49988891-G-A

Variant names:

• chr10-49988891-G-A
• NM_001077665.3:c.176G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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]

ENSG00000285803 (HGNC:):

ACMG classification

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
AGAP6	NM_001077665.3	c.176G>A	p.Gly59Asp	missense_variant	Exon 1 of 8	ENST00000412531.7	NP_001071133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP6	ENST00000412531.7	c.176G>A	p.Gly59Asp	missense_variant	Exon 1 of 8	1	NM_001077665.3	ENSP00000500374.1
TIMM23B-AGAP6	ENST00000651763.1	n.*391G>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502214.1
TIMM23B-AGAP6	ENST00000651763.1	n.*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

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

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;