15-67209444-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024666.5(AAGAB):c.618+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,601,580 control chromosomes in the GnomAD database, including 56,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6372 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49643 hom.)
• Consequence: AAGAB NM_024666.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.489

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-67209444-T-C is Benign according to our data. Variant chr15-67209444-T-C is described in ClinVar as [Benign]. Clinvar id is 1280017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAGAB	NM_024666.5	c.618+18A>G		intron_variant		ENST00000261880.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10	c.618+18A>G		intron_variant		1	NM_024666.5	P1
AAGAB	ENST00000542650.5	c.291+18A>G		intron_variant		2
AAGAB	ENST00000561452.5	c.291+18A>G		intron_variant		5
AAGAB	ENST00000538028.1	n.299+18A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43611 AN: 151978 Hom.: 6372 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.284

GnomAD3 exomes AF: 0.288 AC: 71426 AN: 247870 Hom.: 10880 AF XY: 0.287 AC XY: 38604 AN XY: 134504

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.257 AC: 372969 AN: 1449484 Hom.: 49643 Cov.: 29 AF XY: 0.260 AC XY: 187952 AN XY: 721834

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.368

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.362

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.287 AC: 43630 AN: 152096 Hom.: 6372 Cov.: 32 AF XY: 0.289 AC XY: 21484 AN XY: 74346

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.283

Alfa AF: 0.205 Hom.: 905

Bravo AF: 0.291

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Palmoplantar keratoderma, punctate type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.20
Dann	Benign	0.82

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: rs28693872; hg19: chr15-67501782; COSMIC: COSV56015976;