chr15-67228279-T-C

Variant names:

• chr15-67228279-T-C
• rs4776906
• NM_024666.5:c.535+3535A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024666.5(AAGAB):​c.535+3535A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,216 control chromosomes in the GnomAD database, including 4,130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4130 hom., cov: 33)
• Consequence: AAGAB NM_024666.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450
• Publications: 8 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• punctate palmoplantar keratoderma type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024666.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAGAB	NM_024666.5	MANE Select	c.535+3535A>G		intron	N/A	NP_078942.3
	AAGAB	NM_001271885.2		c.208+3535A>G		intron	N/A	NP_001258814.1	Q6PD74-2
	AAGAB	NM_001271886.2		c.208+3535A>G		intron	N/A	NP_001258815.1	Q6PD74-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAGAB	ENST00000261880.10	TSL:1 MANE Select	c.535+3535A>G		intron	N/A	ENSP00000261880.5	Q6PD74-1
	AAGAB	ENST00000947778.1		c.535+3535A>G		intron	N/A	ENSP00000617837.1
	AAGAB	ENST00000902812.1		c.523+3535A>G		intron	N/A	ENSP00000572871.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32478 AN: 152098 Hom.: 4125 Cov.: 33

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.214 AC: 32512 AN: 152216 Hom.: 4130 Cov.: 33 AF XY: 0.218 AC XY: 16235 AN XY: 74428

African (AFR) AF: 0.100 AC: 4173 AN: 41554

American (AMR) AF: 0.323 AC: 4941 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1263 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2437 AN: 5178

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10580

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15528 AN: 68004

Other (OTH) AF: 0.249 AC: 526 AN: 2112

Alfa AF: 0.112 Hom.: 181

Bravo AF: 0.220

Asia WGS AF: 0.359 AC: 1248 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		0.45
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: rs4776906; hg19: chr15-67520617;