Variant 15-67203564-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024666.5(AAGAB):c.854A>C(p.Lys285Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

AAGAB
NM_024666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AAGAB	NM_024666.5 linkuse as main transcript	c.854A>C	p.Lys285Thr	missense_variant	9/10	ENST00000261880.10
AAGAB	NM_001271885.2 linkuse as main transcript	c.527A>C	p.Lys176Thr	missense_variant	9/10
AAGAB	NM_001271886.2 linkuse as main transcript	c.527A>C	p.Lys176Thr	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10 linkuse as main transcript	c.854A>C	p.Lys285Thr	missense_variant	9/10	1	NM_024666.5	P1	Q6PD74-1
AAGAB	ENST00000542650.5 linkuse as main transcript	c.527A>C	p.Lys176Thr	missense_variant	9/10	2			Q6PD74-2
AAGAB	ENST00000561452.5 linkuse as main transcript	c.527A>C	p.Lys176Thr	missense_variant	9/10	5			Q6PD74-2
AAGAB	ENST00000538028.1 linkuse as main transcript	n.535A>C		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.854A>C (p.K285T) alteration is located in exon 9 (coding exon 9) of the AAGAB gene. This alteration results from a A to C substitution at nucleotide position 854, causing the lysine (K) at amino acid position 285 to be replaced by a threonine (T). 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

0.94

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.94

MutPred

0.60

Loss of methylation at K285 (P = 8e-04);.;.;

MVP

0.77

MPC

0.082

ClinPred

1.0

GERP RS

5.2

Varity_R

0.85

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over