rs199702315

Positions:

• chr5-78101011-TTTC-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The ENST00000255194.11(AP3B1):​c.2409_2411del​(p.Lys804del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,523,058 control chromosomes in the GnomAD database, including 294 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., cov: 32)
  • Exomes 𝑓: 0.018 (266 hom.)
• Consequence: AP3B1 ENST00000255194.11 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.78

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 5-78101011-TTTC-T is Benign according to our data. Variant chr5-78101011-TTTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 179635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78101011-TTTC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2162/152258) while in subpopulation NFE AF= 0.02 (1358/67960). AF 95% confidence interval is 0.0191. There are 28 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.2409_2411del	p.Lys804del	inframe_deletion	21/27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.2262_2264del	p.Lys755del	inframe_deletion	21/27		NP_001258698.1
AP3B1	NM_001410752.1	c.2409_2411del	p.Lys804del	inframe_deletion	21/23		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.2409_2411del	p.Lys804del	inframe_deletion	21/27	1	NM_003664.5	ENSP00000255194	P2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2165 AN: 152140 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0136 AC: 3069 AN: 226264 Hom.: 36 AF XY: 0.0133 AC XY: 1621 AN XY: 121804

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0175 AC: 24053 AN: 1370800 Hom.: 266 AF XY: 0.0172 AC XY: 11757 AN XY: 684740

Gnomad4 AFR exome AF: 0.00286

Gnomad4 AMR exome AF: 0.00605

Gnomad4 ASJ exome AF: 0.00489

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.0362

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0142 AC: 2162 AN: 152258 Hom.: 28 Cov.: 32 AF XY: 0.0142 AC XY: 1056 AN XY: 74454

Gnomad4 AFR AF: 0.00394

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0330

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0154 Hom.: 5

Bravo AF: 0.0123

Asia WGS AF: 0.00145 AC: 5 AN: 3458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2014

Lys804del in exon 21 of AP3B1: This variant is not expected to have clinical sig nificance because it has been identified in 1.85% (161/8721) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs199702315). -

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2020

- -

Hermansky-Pudlak syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

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: rs199702315; hg19: chr5-77396835;