10-49991696-G-A

Variant names:

• chr10-49991696-G-A
• rs782153811
• NM_001077665.3:c.313G>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.313G>A​(p.Ala105Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000732 in 1,597,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: AGAP6 NM_001077665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

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]

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=0.13648096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP6	NM_001077665.3	c.313G>A	p.Ala105Thr	missense_variant	Exon 3 of 8	ENST00000412531.7	NP_001071133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP6	ENST00000412531.7	c.313G>A	p.Ala105Thr	missense_variant	Exon 3 of 8	1	NM_001077665.3	ENSP00000500374.1
TIMM23B-AGAP6	ENST00000651763.1	n.*528G>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502214.1
TIMM23B-AGAP6	ENST00000651763.1	n.*528G>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502214.1

Frequencies

GnomAD3 genomes AF: 0.0000727 AC: 11 AN: 151294 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

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: 0.0000589

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.0000784 AC: 18 AN: 229520 Hom.: 0 AF XY: 0.0000795 AC XY: 10 AN XY: 125730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000730

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000733 AC: 106 AN: 1446554 Hom.: 0 Cov.: 30 AF XY: 0.0000736 AC XY: 53 AN XY: 720014

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000380

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: 0.0000783

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000727 AC: 11 AN: 151294 Hom.: 0 Cov.: 30 AF XY: 0.0000677 AC XY: 5 AN XY: 73802

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.000962

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000502 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313G>A (p.A105T) alteration is located in exon 3 (coding exon 3) of the AGAP6 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the alanine (A) at amino acid position 105 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0032	T;.
Eigen	Benign	-0.0084
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.45	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.082	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.041
MVP		0.38
ClinPred		0.53	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs782153811; hg19: chr10-51751456;