rs4532349

chr5-78177341-A-G

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.1038T>C(p.Asn346=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,604,018 control chromosomes in the GnomAD database, including 38,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2847 hom., cov: 32)
  • Exomes 𝑓: 0.21 (35352 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.001395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.11

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=-0.36).
• BP6: Variant 5-78177341-A-G is Benign according to our data. Variant chr5-78177341-A-G is described in ClinVar as [Benign]. Clinvar id is 178705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78177341-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5	c.1038T>C	p.Asn346=	splice_region_variant, synonymous_variant	9/27	ENST00000255194.11
AP3B1	NM_001271769.2	c.891T>C	p.Asn297=	splice_region_variant, synonymous_variant	9/27
AP3B1	NM_001410752.1	c.1038T>C	p.Asn346=	splice_region_variant, synonymous_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11	c.1038T>C	p.Asn346=	splice_region_variant, synonymous_variant	9/27	1	NM_003664.5	P2

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27948 AN: 152022 Hom.: 2843 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0694

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.194 AC: 48604 AN: 251172 Hom.: 5258 AF XY: 0.188 AC XY: 25543 AN XY: 135744

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.0598

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.214 AC: 310203 AN: 1451880 Hom.: 35352 Cov.: 29 AF XY: 0.211 AC XY: 152200 AN XY: 722954

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.0748

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.184 AC: 27972 AN: 152138 Hom.: 2847 Cov.: 32 AF XY: 0.182 AC XY: 13499 AN XY: 74374

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.0688

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.187

Alfa AF: 0.212 Hom.: 4525

Bravo AF: 0.187

Asia WGS AF: 0.126 AC: 438 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.219

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2013	Benign based on MAF (12-22% in ESP populations) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hermansky-Pudlak syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.010
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: rs4532349; hg19: chr5-77473165; COSMIC: COSV54880120;