15-67204120-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024666.5(AAGAB):c.744A>T(p.Glu248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,610,656 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: AAGAB NM_024666.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.62

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03526506).
• BP6: Variant 15-67204120-T-A is Benign according to our data. Variant chr15-67204120-T-A is described in ClinVar as [Benign]. Clinvar id is 2763265.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000137 (200/1458436) while in subpopulation AMR AF= 0.000382 (17/44520). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAGAB	NM_024666.5	c.744A>T	p.Glu248Asp	missense_variant	8/10	ENST00000261880.10
AAGAB	NM_001271885.2	c.417A>T	p.Glu139Asp	missense_variant	8/10
AAGAB	NM_001271886.2	c.417A>T	p.Glu139Asp	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10	c.744A>T	p.Glu248Asp	missense_variant	8/10	1	NM_024666.5	P1
AAGAB	ENST00000542650.5	c.417A>T	p.Glu139Asp	missense_variant	8/10	2
AAGAB	ENST00000561452.5	c.417A>T	p.Glu139Asp	missense_variant	8/10	5
AAGAB	ENST00000538028.1	n.425A>T		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000278 AC: 69 AN: 248448 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1458436 Hom.: 0 Cov.: 29 AF XY: 0.000134 AC XY: 97 AN XY: 725704

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.00445

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74372

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 23, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0019	T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;T;T
Sift4G	Benign	0.20	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.65
MutPred		0.59		Gain of disorder (P = 0.1976);.;.;
MVP		0.20
MPC		0.082
ClinPred		0.11	T
GERP RS		1.7
Varity_R		0.39
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs372325047; hg19: chr15-67496458; COSMIC: COSV56017392;