NM_003664.5:c.280-6dupT

Variant names:

• chr5-78228244-T-TA
• rs5868908
• NM_003664.5:c.280-6dupT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003664.5(AP3B1):​c.280-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,555,402 control chromosomes in the GnomAD database, including 67,140 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8529 hom., cov: 0)
  • Exomes 𝑓: 0.31 (58611 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.10

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 -16 ACMG points.

• BP6: Variant 5-78228244-T-TA is Benign according to our data. Variant chr5-78228244-T-TA is described in ClinVar as [Benign]. Clinvar id is 354253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.280-6dupT		splice_region_variant, intron_variant	Intron 3 of 26	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.133-6dupT		splice_region_variant, intron_variant	Intron 3 of 26		NP_001258698.1
AP3B1	NM_001410752.1	c.280-6dupT		splice_region_variant, intron_variant	Intron 3 of 22		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.280-6_280-5insT		splice_region_variant, intron_variant	Intron 3 of 26	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50595 AN: 151412 Hom.: 8523 Cov.: 0

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.309 AC: 69101 AN: 223498 Hom.: 8630 AF XY: 0.311 AC XY: 37700 AN XY: 121230

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.308 AC: 432770 AN: 1403874 Hom.: 58611 Cov.: 26 AF XY: 0.309 AC XY: 215933 AN XY: 699546

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.372

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.334 AC: 50634 AN: 151528 Hom.: 8529 Cov.: 0 AF XY: 0.332 AC XY: 24602 AN XY: 74018

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.323

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 52% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Hermansky-Pudlak syndrome 2 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs5868908; hg19: chr5-77524068;