Genetic Variant AGAP6:p.Val49Val (chr10-49988862-A-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001077665.3(AGAP6):c.147A>G(p.Val49Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,593,090 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

AGAP6
NM_001077665.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.165

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]

AGAP6 links:

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]

TIMM23B-AGAP6 links:

ENSG00000285803 (HGNC:):

ENSG00000285803 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 10-49988862-A-G is Benign according to our data. Variant chr10-49988862-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2640466.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.165 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP6	NM_001077665.3 link	c.147A>G	p.Val49Val	synonymous_variant	Exon 1 of 8	ENST00000412531.7	NP_001071133.2	Q5VW22-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGAP6	ENST00000412531.7 link	c.147A>G	p.Val49Val	synonymous_variant	Exon 1 of 8	1	NM_001077665.3	ENSP00000500374.1	Q5VW22-2
TIMM23B-AGAP6	ENST00000651763.1 link	n.*362A>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502214.1
TIMM23B-AGAP6	ENST00000651763.1 link	n.*362A>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502214.1

Frequencies

GnomAD3 genomes

AF:

0.000262

AC:

AN:

149046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00158

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.0000974

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000254

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00146

AC:

AN:

21292

Hom.:

AF XY:

0.00110

AC XY:

AN XY:

10928

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00628

Gnomad EAS exome

AF:

0.000325

Gnomad SAS exome

AF:

0.00590

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000718

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000261

AC:

377

AN:

1443942

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

234

AN XY:

718880

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00147

Gnomad4 FIN exome

AF:

0.000173

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000250

GnomAD4 genome

AF:

0.000248

AC:

AN:

149148

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

AN XY:

72740

show subpopulations

Gnomad4 AFR

AF:

0.0000984

Gnomad4 AMR

AF:

0.000201

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00139

Gnomad4 SAS

AF:

0.00107

Gnomad4 FIN

AF:

0.0000974

Gnomad4 NFE

AF:

0.000254

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000474

Hom.:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGAP6: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.9

DANN

Benign

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over