15-67208595-T-C

Variant names:

• chr15-67208595-T-C
• rs36096355
• NM_024666.5:c.682A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.439
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 776916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 864 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAGAB	NM_024666.5	MANE Select	c.682A>G	p.Asn228Asp	missense	Exon 7 of 10	NP_078942.3
	AAGAB	NM_001271885.2		c.355A>G	p.Asn119Asp	missense	Exon 7 of 10	NP_001258814.1	Q6PD74-2
	AAGAB	NM_001271886.2		c.355A>G	p.Asn119Asp	missense	Exon 7 of 10	NP_001258815.1	Q6PD74-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAGAB	ENST00000261880.10	TSL:1 MANE Select	c.682A>G	p.Asn228Asp	missense	Exon 7 of 10	ENSP00000261880.5	Q6PD74-1
	AAGAB	ENST00000947778.1		c.730A>G	p.Asn244Asp	missense	Exon 8 of 11	ENSP00000617837.1
	AAGAB	ENST00000902812.1		c.670A>G	p.Asn224Asp	missense	Exon 7 of 10	ENSP00000572871.1

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

GnomAD2 exomes AF: 0.00140 AC: 350 AN: 249538 AF XY: 0.00108

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 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

African (AFR) AF: 0.0219 AC: 732 AN: 33478

American (AMR) AF: 0.00132 AC: 59 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111978

Other (OTH) AF: 0.00157 AC: 95 AN: 60396

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

African (AFR) AF: 0.0196 AC: 816 AN: 41574

American (AMR) AF: 0.00222 AC: 34 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00208 Hom.: 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.44
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.037
Sift	Benign	0.64	T
Sift4G	Benign	0.87	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs36096355; hg19: chr15-67500933;