15-67204071-G-A

Variant names:

• chr15-67204071-G-A
• NM_024666.5:c.793C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024666.5(AAGAB):​c.793C>T​(p.Leu265Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AAGAB NM_024666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAGAB	NM_024666.5	c.793C>T	p.Leu265Phe	missense_variant	Exon 8 of 10	ENST00000261880.10	NP_078942.3
AAGAB	NM_001271885.2	c.466C>T	p.Leu156Phe	missense_variant	Exon 8 of 10		NP_001258814.1
AAGAB	NM_001271886.2	c.466C>T	p.Leu156Phe	missense_variant	Exon 8 of 10		NP_001258815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAGAB	ENST00000261880.10	c.793C>T	p.Leu265Phe	missense_variant	Exon 8 of 10	1	NM_024666.5	ENSP00000261880.5
AAGAB	ENST00000542650.5	c.466C>T	p.Leu156Phe	missense_variant	Exon 8 of 10	2		ENSP00000440735.1
AAGAB	ENST00000561452.5	c.466C>T	p.Leu156Phe	missense_variant	Exon 8 of 10	5		ENSP00000453263.1
AAGAB	ENST00000538028.1	n.474C>T		non_coding_transcript_exon_variant	Exon 5 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.793C>T (p.L265F) alteration is located in exon 8 (coding exon 8) of the AAGAB gene. This alteration results from a C to T substitution at nucleotide position 793, causing the leucine (L) at amino acid position 265 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.10	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.79		Gain of methylation at K270 (P = 0.0857);.;.;
MVP		0.65
MPC		0.082
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.32
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-67496409;