15-67236036-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024666.5(AAGAB):c.394A>C(p.Ile132Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,610,922 control chromosomes in the GnomAD database, including 97,347 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I132V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.29 ( 7759 hom., cov: 32)

Exomes 𝑓: 0.34 ( 89588 hom. )

Consequence

AAGAB
NM_024666.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.02

Publications

51 publications found

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 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

AAGAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.320395E-6).

BP6

Variant 15-67236036-T-G is Benign according to our data. Variant chr15-67236036-T-G is described in ClinVar as Benign. ClinVar VariationId is 803103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AAGAB	NM_024666.5	MANE Select	c.394A>C	p.Ile132Leu	missense	Exon 4 of 10	NP_078942.3
AAGAB	NM_001271885.2		c.67A>C	p.Ile23Leu	missense	Exon 4 of 10	NP_001258814.1	Q6PD74-2
AAGAB	NM_001271886.2		c.67A>C	p.Ile23Leu	missense	Exon 4 of 10	NP_001258815.1	Q6PD74-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AAGAB	ENST00000261880.10	TSL:1 MANE Select	c.394A>C	p.Ile132Leu	missense	Exon 4 of 10	ENSP00000261880.5	Q6PD74-1
AAGAB	ENST00000947778.1		c.394A>C	p.Ile132Leu	missense	Exon 4 of 11	ENSP00000617837.1
AAGAB	ENST00000902812.1		c.394A>C	p.Ile132Leu	missense	Exon 4 of 10	ENSP00000572871.1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43822

AN:

151992

Hom.:

7756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.421

Gnomad EAS

AF:

0.659

Gnomad SAS

AF:

0.457

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.370

AC:

92019

AN:

248468

AF XY:

0.374

show subpopulations

Gnomad AFR exome

AF:

0.0936

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.421

Gnomad EAS exome

AF:

0.665

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.327

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.342

AC:

498308

AN:

1458810

Hom.:

89588

Cov.:

AF XY:

0.345

AC XY:

250105

AN XY:

725772

show subpopulations

African (AFR)

AF:

0.0913

AC:

3051

AN:

33424

American (AMR)

AF:

0.402

AC:

17879

AN:

44466

Ashkenazi Jewish (ASJ)

AF:

0.420

AC:

10955

AN:

26096

East Asian (EAS)

AF:

0.645

AC:

25506

AN:

39574

South Asian (SAS)

AF:

0.446

AC:

38372

AN:

85952

European-Finnish (FIN)

AF:

0.361

AC:

19239

AN:

53296

Middle Eastern (MID)

AF:

0.411

AC:

2364

AN:

5758

European-Non Finnish (NFE)

AF:

0.325

AC:

360303

AN:

1109954

Other (OTH)

AF:

0.342

AC:

20639

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

15139

30279

45418

60558

75697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11868

23736

35604

47472

59340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.288

AC:

43837

AN:

152112

Hom.:

7759

Cov.:

AF XY:

0.301

AC XY:

22349

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.100

AC:

4169

AN:

41540

American (AMR)

AF:

0.380

AC:

5806

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

1463

AN:

3472

East Asian (EAS)

AF:

0.660

AC:

3413

AN:

5174

South Asian (SAS)

AF:

0.457

AC:

2200

AN:

4812

European-Finnish (FIN)

AF:

0.377

AC:

3980

AN:

10570

Middle Eastern (MID)

AF:

0.372

AC:

108

AN:

290

European-Non Finnish (NFE)

AF:

0.321

AC:

21805

AN:

67938

Other (OTH)

AF:

0.310

AC:

656

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1476

2952

4428

5904

7380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.323

Hom.:

38169

Bravo

AF:

0.280

TwinsUK

AF:

0.331

AC:

1229

ALSPAC

AF:

0.335

AC:

1291

ESP6500AA

AF:

0.105

AC:

392

ESP6500EA

AF:

0.321

AC:

2639

ExAC

AF:

0.364

AC:

43975

Asia WGS

AF:

0.499

AC:

1734

AN:

3478

EpiCase

AF:

0.336

EpiControl

AF:

0.329

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0035

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0000073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

3.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.58

REVEL

Benign

0.061

Sift

Benign

0.36

Sift4G

Benign

0.23

Polyphen

0.019

Vest4

0.26

MPC

0.080

ClinPred

0.015

GERP RS

5.5

Varity_R

0.21

gMVP

0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over