Variant 15-67204104-T-TG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PP5_ModerateBS2_Supporting

The NM_024666.5(AAGAB):c.759_760insC(p.Thr254HisfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

AAGAB
NM_024666.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.272

Variant links:

Genes affected

AAGAB (HGNC:25662): (alpha and gamma adaptin binding protein) The protein encoded by this gene interacts with the gamma-adaptin and alpha-adaptin subunits of complexes involved in clathrin-coated vesicle trafficking. Mutations in this gene are associated with type I punctate palmoplantar keratoderma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

AAGAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-67204104-T-TG is Pathogenic according to our data. Variant chr15-67204104-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 2872740.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AAGAB	NM_024666.5 linkuse as main transcript	c.759_760insC	p.Thr254HisfsTer10	frameshift_variant	8/10	ENST00000261880.10
AAGAB	NM_001271885.2 linkuse as main transcript	c.432_433insC	p.Thr145HisfsTer10	frameshift_variant	8/10
AAGAB	NM_001271886.2 linkuse as main transcript	c.432_433insC	p.Thr145HisfsTer10	frameshift_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10 linkuse as main transcript	c.759_760insC	p.Thr254HisfsTer10	frameshift_variant	8/10	1	NM_024666.5	P1	Q6PD74-1
AAGAB	ENST00000542650.5 linkuse as main transcript	c.432_433insC	p.Thr145HisfsTer10	frameshift_variant	8/10	2			Q6PD74-2
AAGAB	ENST00000561452.5 linkuse as main transcript	c.432_433insC	p.Thr145HisfsTer10	frameshift_variant	8/10	5			Q6PD74-2
AAGAB	ENST00000538028.1 linkuse as main transcript	n.440_441insC		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248822

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135056

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460194

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726482

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:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change creates a premature translational stop signal (p.Thr254Hisfs*10) in the AAGAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAGAB are known to be pathogenic (PMID: 23000146, 23064416, 23563198, 23633024, 24390136). This variant is present in population databases (rs765401006, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AAGAB-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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