rs66517624

Variant names:

• chr15-67209828-A-T
• rs66517624
• NM_024666.5:c.536-284T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024666.5(AAGAB):​c.536-284T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,084 control chromosomes in the GnomAD database, including 7,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7618 hom., cov: 31)
• Consequence: AAGAB NM_024666.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.594
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• palmoplantar keratoderma, punctate type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• punctate palmoplantar keratoderma type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 15-67209828-A-T is Benign according to our data. Variant chr15-67209828-A-T is described in ClinVar as Benign. ClinVar VariationId is 1284136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAGAB	NM_024666.5	c.536-284T>A		intron_variant	Intron 5 of 9	ENST00000261880.10	NP_078942.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAGAB	ENST00000261880.10	c.536-284T>A		intron_variant	Intron 5 of 9	1	NM_024666.5	ENSP00000261880.5
AAGAB	ENST00000542650.5	c.209-284T>A		intron_variant	Intron 5 of 9	2		ENSP00000440735.1
AAGAB	ENST00000561452.5	c.209-284T>A		intron_variant	Intron 5 of 9	5		ENSP00000453263.1
AAGAB	ENST00000538028.1	n.217-284T>A		intron_variant	Intron 2 of 6	2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47018 AN: 150966 Hom.: 7615 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.303

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.311 AC: 47055 AN: 151084 Hom.: 7618 Cov.: 31 AF XY: 0.312 AC XY: 23037 AN XY: 73740

African (AFR) AF: 0.418 AC: 17148 AN: 41048

American (AMR) AF: 0.318 AC: 4826 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3462

East Asian (EAS) AF: 0.308 AC: 1581 AN: 5140

South Asian (SAS) AF: 0.371 AC: 1765 AN: 4754

European-Finnish (FIN) AF: 0.292 AC: 3033 AN: 10392

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 16988 AN: 67788

Other (OTH) AF: 0.307 AC: 646 AN: 2104

Alfa AF: 0.293 Hom.: 849

Bravo AF: 0.321

Asia WGS AF: 0.361 AC: 1255 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.059
DANN	Benign	0.22
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs66517624; hg19: chr15-67502166;