rs75248449

chr5-78162865-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003664.5(AP3B1):c.1317T>G(p.Thr439=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,614,064 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (32 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.928

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-78162865-A-C is Benign according to our data. Variant chr5-78162865-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178704.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr5-78162865-A-C is described in Lovd as [Benign]. Variant chr5-78162865-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.928 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00516 (786/152342) while in subpopulation AMR AF= 0.0123 (189/15310). AF 95% confidence interval is 0.0109. There are 0 homozygotes in gnomad4. There are 379 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5	c.1317T>G	p.Thr439=	synonymous_variant	13/27	ENST00000255194.11
AP3B1	NM_001271769.2	c.1170T>G	p.Thr390=	synonymous_variant	13/27
AP3B1	NM_001410752.1	c.1317T>G	p.Thr439=	synonymous_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11	c.1317T>G	p.Thr439=	synonymous_variant	13/27	1	NM_003664.5	P2

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 787 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00460 AC: 1156 AN: 251326 Hom.: 3 AF XY: 0.00451 AC XY: 612 AN XY: 135824

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00553 AC: 8082 AN: 1461722 Hom.: 32 Cov.: 31 AF XY: 0.00538 AC XY: 3911 AN XY: 727166

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.00579

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00509 AC XY: 379 AN XY: 74496

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00561 Hom.: 1

Bravo AF: 0.00514

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr439Thr in exon 13 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 0.5% (47/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs75248449). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2018	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AP3B1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hermansky-Pudlak syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.28
Dann	Benign	0.37

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: rs75248449; hg19: chr5-77458689;