rs17192146

Positions:

• chr5-78129275-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003664.5(AP3B1):​c.1683C>T​(p.Leu561=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,612,396 control chromosomes in the GnomAD database, including 3,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (269 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3420 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.97

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-78129275-G-A is Benign according to our data. Variant chr5-78129275-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5	c.1683C>T	p.Leu561=	synonymous_variant	16/27	ENST00000255194.11
AP3B1	NM_001271769.2	c.1536C>T	p.Leu512=	synonymous_variant	16/27
AP3B1	NM_001410752.1	c.1683C>T	p.Leu561=	synonymous_variant	16/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11	c.1683C>T	p.Leu561=	synonymous_variant	16/27	1	NM_003664.5	P2

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7085 AN: 151958 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0605

GnomAD3 exomes AF: 0.0524 AC: 13173 AN: 251214 Hom.: 435 AF XY: 0.0548 AC XY: 7440 AN XY: 135790

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0802

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0534

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0649 AC: 94767 AN: 1460320 Hom.: 3420 Cov.: 34 AF XY: 0.0651 AC XY: 47296 AN XY: 726520

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.0813

Gnomad4 EAS exome AF: 0.000656

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.0385

Gnomad4 NFE exome AF: 0.0721

Gnomad4 OTH exome AF: 0.0600

GnomAD4 genome AF: 0.0466 AC: 7081 AN: 152076 Hom.: 269 Cov.: 32 AF XY: 0.0451 AC XY: 3351 AN XY: 74352

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0511

Gnomad4 ASJ AF: 0.0737

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.0709

Gnomad4 OTH AF: 0.0594

Alfa AF: 0.0631 Hom.: 232

Bravo AF: 0.0479

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0708

EpiControl AF: 0.0707

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu561Leu in exon 16 of AP3B1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 6.8% (587/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17192146). -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.73

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: rs17192146; hg19: chr5-77425099;