15-67208595-T-C

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.682A>G(p.Asn228Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,174 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (15 hom.)
• Consequence: AAGAB NM_024666.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.439

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=0.003647536).
• BP6: Variant 15-67208595-T-C is Benign according to our data. Variant chr15-67208595-T-C is described in ClinVar as [Benign]. Clinvar id is 776916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00567 (864/152324) while in subpopulation AFR AF= 0.0196 (816/41574). AF 95% confidence interval is 0.0185. There are 6 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 860 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAGAB	NM_024666.5	c.682A>G	p.Asn228Asp	missense_variant	7/10	ENST00000261880.10
AAGAB	NM_001271885.2	c.355A>G	p.Asn119Asp	missense_variant	7/10
AAGAB	NM_001271886.2	c.355A>G	p.Asn119Asp	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAGAB	ENST00000261880.10	c.682A>G	p.Asn228Asp	missense_variant	7/10	1	NM_024666.5	P1
AAGAB	ENST00000542650.5	c.355A>G	p.Asn119Asp	missense_variant	7/10	2
AAGAB	ENST00000561452.5	c.355A>G	p.Asn119Asp	missense_variant	7/10	5
AAGAB	ENST00000538028.1	n.363A>G		non_coding_transcript_exon_variant	4/7	2

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152206 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00140 AC: 350 AN: 249538 Hom.: 8 AF XY: 0.00108 AC XY: 146 AN XY: 135380

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000717 AC: 1048 AN: 1461850 Hom.: 15 Cov.: 31 AF XY: 0.000638 AC XY: 464 AN XY: 727230

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152324 Hom.: 6 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74490

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000987 Hom.: 2

Bravo AF: 0.00648

ESP6500AA AF: 0.0179 AC: 69

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00161 AC: 194

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.6
Dann	Benign	0.31
DEOGEN2	Benign	0.0012	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.55	T;.;T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.87	T;T;T
Polyphen		0.053	B;.;.
Vest4		0.083
MVP		0.040
MPC		0.012
ClinPred		0.0060	T
GERP RS		0.33
Varity_R		0.047
gMVP		0.11

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

Other links and lift over

dbSNP: rs36096355; hg19: chr15-67500933;