15-67236060-G-T

Variant names:

• chr15-67236060-G-T
• rs200564757
• NM_024666.5:c.370C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_024666.5(AAGAB):​c.370C>A​(p.Arg124Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AAGAB NM_024666.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 11 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=3.06 with no splicing effect.

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.370C>A	p.Arg124Arg	synonymous	Exon 4 of 10	NP_078942.3
	AAGAB	NM_001271885.2		c.43C>A	p.Arg15Arg	synonymous	Exon 4 of 10	NP_001258814.1	Q6PD74-2
	AAGAB	NM_001271886.2		c.43C>A	p.Arg15Arg	synonymous	Exon 4 of 10	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.370C>A	p.Arg124Arg	synonymous	Exon 4 of 10	ENSP00000261880.5	Q6PD74-1
	AAGAB	ENST00000947778.1		c.370C>A	p.Arg124Arg	synonymous	Exon 4 of 11	ENSP00000617837.1
	AAGAB	ENST00000902812.1		c.370C>A	p.Arg124Arg	synonymous	Exon 4 of 10	ENSP00000572871.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456710 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724854

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108458

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.6
DANN	Benign	0.73
PhyloP100		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs200564757; hg19: chr15-67528398;