5-78015515-ACAG-A

Position:

• chr5-78015515-ACAG-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The ENST00000255194.11(AP3B1):​c.3023_3025del​(p.Ala1008del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,613,790 control chromosomes in the GnomAD database, including 528 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (270 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (258 hom.)
• Consequence: AP3B1 ENST00000255194.11 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.30

Genes affected

AP3B1 (HGNC:566): (adaptor related protein complex 3 subunit beta 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is part of the heterotetrameric AP-3 protein complex which interacts with the scaffolding protein clathrin. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000255194.11. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-78015515-ACAG-A is Benign according to our data. Variant chr5-78015515-ACAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 226459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78015515-ACAG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.3023_3025del	p.Ala1008del	inframe_deletion	26/27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.2876_2878del	p.Ala959del	inframe_deletion	26/27		NP_001258698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.3023_3025del	p.Ala1008del	inframe_deletion	26/27	1	NM_003664.5	ENSP00000255194	P2

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5017 AN: 152124 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.00887 AC: 2230 AN: 251412 Hom.: 113 AF XY: 0.00645 AC XY: 876 AN XY: 135872

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00351 AC: 5125 AN: 1461548 Hom.: 258 AF XY: 0.00308 AC XY: 2240 AN XY: 727076

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.00717

GnomAD4 genome AF: 0.0330 AC: 5025 AN: 152242 Hom.: 270 Cov.: 32 AF XY: 0.0320 AC XY: 2384 AN XY: 74444

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.00466 Hom.: 16

Bravo AF: 0.0378

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 22, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 09, 2015

p.Ala1008del in exon 26 of AP3B1: This variant is not expected to have clinical significance because it has been identified in 12.02% (1251/10404) of African ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs111935323). -

Hermansky-Pudlak syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2018

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111935323; hg19: chr5-77311339;