15-67204051-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024666.5(AAGAB):c.813A>T(p.Glu271Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AAGAB NM_024666.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3125639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAGAB	NM_024666.5	c.813A>T	p.Glu271Asp	missense_variant	8/10	ENST00000261880.10
AAGAB	NM_001271885.2	c.486A>T	p.Glu162Asp	missense_variant	8/10
AAGAB	NM_001271886.2	c.486A>T	p.Glu162Asp	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10	c.813A>T	p.Glu271Asp	missense_variant	8/10	1	NM_024666.5	P1
AAGAB	ENST00000542650.5	c.486A>T	p.Glu162Asp	missense_variant	8/10	2
AAGAB	ENST00000561452.5	c.486A>T	p.Glu162Asp	missense_variant	8/10	5
AAGAB	ENST00000538028.1	n.494A>T		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439856 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 717712

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2023

The c.813A>T (p.E271D) alteration is located in exon 8 (coding exon 8) of the AAGAB gene. This alteration results from a A to T substitution at nucleotide position 813, causing the glutamic acid (E) at amino acid position 271 to be replaced by an aspartic acid (D). 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	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0065	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.53
MutPred		0.48		Loss of ubiquitination at K273 (P = 0.0603);.;.;
MVP		0.19
MPC		0.082
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.19

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: chr15-67496389;