rs146503597

Variant names:

• chr5-78015546-C-T
• rs146503597
• NM_003664.5:c.2995G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003664.5(AP3B1):​c.2995G>A​(p.Val999Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,613,418 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (61 hom.)
• Consequence: AP3B1 NM_003664.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.42
• Publications: 10 publications found

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]

AP3B1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007074684).
• BP6: Variant 5-78015546-C-T is Benign according to our data. Variant chr5-78015546-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195962.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00499 (759/152166) while in subpopulation AMR AF = 0.0105 (161/15276). AF 95% confidence interval is 0.00921. There are 3 homozygotes in GnomAd4. There are 357 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003664.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.2995G>A	p.Val999Met	missense splice_region	Exon 26 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2848G>A	p.Val950Met	missense splice_region	Exon 26 of 27	NP_001258698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2995G>A	p.Val999Met	missense splice_region	Exon 26 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.2848G>A	p.Val950Met	missense splice_region	Exon 26 of 27	ENSP00000430597.1
	AP3B1	ENST00000695511.1		c.2995G>A	p.Val999Met	missense splice_region	Exon 26 of 28	ENSP00000511974.1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152048 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00312

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00413 AC: 1038 AN: 251256 AF XY: 0.00416

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.00662

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00704 AC: 10291 AN: 1461252 Hom.: 61 Cov.: 30 AF XY: 0.00683 AC XY: 4963 AN XY: 726898

African (AFR) AF: 0.000986 AC: 33 AN: 33460

American (AMR) AF: 0.00411 AC: 184 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86200

European-Finnish (FIN) AF: 0.00270 AC: 144 AN: 53342

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00850 AC: 9453 AN: 1111652

Other (OTH) AF: 0.00750 AC: 453 AN: 60366

GnomAD4 genome AF: 0.00499 AC: 759 AN: 152166 Hom.: 3 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74404

African (AFR) AF: 0.00166 AC: 69 AN: 41508

American (AMR) AF: 0.0105 AC: 161 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00312 AC: 33 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00649 Hom.: 12

Bravo AF: 0.00537

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00380 AC: 462

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00753

EpiControl AF: 0.00640

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

May 08, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hermansky-Pudlak syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hermansky-Pudlak syndrome 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP3B1: BP4, BS2

Autoinflammatory syndrome Benign:1

Aug 17, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		2.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.072
Sift	Benign	0.33	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.13
MPC		0.043
ClinPred		0.0065	T
GERP RS		-0.17
Varity_R		0.024
gMVP		0.12
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs146503597; hg19: chr5-77311370; COSMIC: COSV99079484;