chr15-67203588-G-A

Position:

chr15-67203588-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_024666.5(AAGAB):c.830C>T(p.Ala277Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,613,236 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: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

AAGAB
NM_024666.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.88

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32697576).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000191 (29/152110) while in subpopulation SAS AF= 0.000414 (2/4826). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AAGAB	NM_024666.5 linkuse as main transcript	c.830C>T	p.Ala277Val	missense_variant	9/10	ENST00000261880.10
AAGAB	NM_001271885.2 linkuse as main transcript	c.503C>T	p.Ala168Val	missense_variant	9/10
AAGAB	NM_001271886.2 linkuse as main transcript	c.503C>T	p.Ala168Val	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10 linkuse as main transcript	c.830C>T	p.Ala277Val	missense_variant	9/10	1	NM_024666.5	P1	Q6PD74-1
AAGAB	ENST00000542650.5 linkuse as main transcript	c.503C>T	p.Ala168Val	missense_variant	9/10	2			Q6PD74-2
AAGAB	ENST00000561452.5 linkuse as main transcript	c.503C>T	p.Ala168Val	missense_variant	9/10	5			Q6PD74-2
AAGAB	ENST00000538028.1 linkuse as main transcript	n.511C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000181

AC:

AN:

248942

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000268

AC:

392

AN:

1461126

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000753

Gnomad4 NFE exome

AF:

0.000311

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000191

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000732

AC:

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

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

Jun 24, 2022

The c.830C>T (p.A277V) alteration is located in exon 9 (coding exon 9) of the AAGAB gene. This alteration results from a C to T substitution at nucleotide position 830, causing the alanine (A) at amino acid position 277 to be replaced by a valine (V). 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

0.28

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.046

D;D;D

Sift4G

Uncertain

0.037

D;T;T

Polyphen

1.0

D;.;.

Vest4

0.50

MVP

0.49

MPC

0.082

ClinPred

0.25

GERP RS

5.2

Varity_R

0.29

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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