5-78039267-G-T

Variant names:

• chr5-78039267-G-T
• rs146624866
• NM_003664.5:c.2585C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003664.5(AP3B1):​c.2585C>A​(p.Thr862Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T862I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3490975).

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.2585C>A	p.Thr862Asn	missense	Exon 23 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2438C>A	p.Thr813Asn	missense	Exon 23 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.2585C>A	p.Thr862Asn	missense	Exon 23 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.2438C>A	p.Thr813Asn	missense	Exon 23 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.2585C>A	p.Thr862Asn	missense	Exon 23 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Uncertain:1

Sep 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 862 of the AP3B1 protein (p.Thr862Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AP3B1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.027
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.054	T
Sift4G	Benign	0.22	T
Polyphen		0.22	B
Vest4		0.40
MutPred		0.65		Loss of glycosylation at T862 (P = 0.0169)
MVP		0.45
MPC		0.12
ClinPred		0.49	T
GERP RS		5.8
PromoterAI		-0.014	Neutral
Varity_R		0.10
gMVP		0.30
Mutation Taster		=86/14	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: rs146624866; hg19: chr5-77335091;