15-67204091-T-A

Variant summary

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

The NM_024666.5(AAGAB):c.773A>T(p.Asp258Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 7.23

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, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAGAB	NM_024666.5	c.773A>T	p.Asp258Val	missense_variant	8/10	ENST00000261880.10
AAGAB	NM_001271885.2	c.446A>T	p.Asp149Val	missense_variant	8/10
AAGAB	NM_001271886.2	c.446A>T	p.Asp149Val	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10	c.773A>T	p.Asp258Val	missense_variant	8/10	1	NM_024666.5	P1
AAGAB	ENST00000542650.5	c.446A>T	p.Asp149Val	missense_variant	8/10	2
AAGAB	ENST00000561452.5	c.446A>T	p.Asp149Val	missense_variant	8/10	5
AAGAB	ENST00000538028.1	n.454A>T		non_coding_transcript_exon_variant	5/7	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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 258 of the AAGAB protein (p.Asp258Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AAGAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2096600). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.94
MutPred		0.65		Loss of loop (P = 0.0288);.;.;
MVP		0.70
MPC		0.079
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.53

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: chr15-67496429;