10-50008844-C-A

Variant names:

• chr10-50008844-C-A
• rs1554864549
• NM_001077665.3:c.719C>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.719C>A​(p.Pro240His) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: AGAP6 NM_001077665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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=0.18720269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP6	NM_001077665.3	c.719C>A	p.Pro240His	missense_variant	Exon 8 of 8	ENST00000412531.7	NP_001071133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP6	ENST00000412531.7	c.719C>A	p.Pro240His	missense_variant	Exon 8 of 8	1	NM_001077665.3	ENSP00000500374.1
TIMM23B-AGAP6	ENST00000651763.1	n.*934C>A		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502214.1
TIMM23B-AGAP6	ENST00000651763.1	n.*934C>A		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502214.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000202 AC: 3 AN: 148866 Hom.: 0 AF XY: 0.0000249 AC XY: 2 AN XY: 80278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.719C>A (p.P240H) alteration is located in exon 8 (coding exon 8) of the AGAP6 gene. This alteration results from a C to A substitution at nucleotide position 719, causing the proline (P) at amino acid position 240 to be replaced by a histidine (H). 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	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.16
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.24
MVP		0.20
ClinPred		0.85	D
GERP RS		0.046
Varity_R		0.43

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: rs1554864549; hg19: chr10-51768604;