5-78110280-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003664.5(AP3B1):c.2324T>A(p.Ile775Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,609,122 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I775T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (5 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.744

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002162218).
• BP6: Variant 5-78110280-A-T is Benign according to our data. Variant chr5-78110280-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 354230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78110280-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0067 (1020/152316) while in subpopulation AFR AF= 0.0233 (967/41570). AF 95% confidence interval is 0.022. There are 10 homozygotes in gnomad4. There are 478 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B1	NM_003664.5	c.2324T>A	p.Ile775Lys	missense_variant	20/27	ENST00000255194.11
AP3B1	NM_001271769.2	c.2177T>A	p.Ile726Lys	missense_variant	20/27
AP3B1	NM_001410752.1	c.2324T>A	p.Ile775Lys	missense_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B1	ENST00000255194.11	c.2324T>A	p.Ile775Lys	missense_variant	20/27	1	NM_003664.5	P2

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1022 AN: 152198 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00175 AC: 427 AN: 243744 Hom.: 4 AF XY: 0.00128 AC XY: 168 AN XY: 131528

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.000734

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.000835

GnomAD4 exome AF: 0.000624 AC: 909 AN: 1456806 Hom.: 5 Cov.: 29 AF XY: 0.000529 AC XY: 383 AN XY: 724352

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.000787

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00670 AC: 1020 AN: 152316 Hom.: 10 Cov.: 32 AF XY: 0.00642 AC XY: 478 AN XY: 74484

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00716

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00231 AC: 281

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile775Lys in exon 20 of AP3B1: This variant is not expected to have clinical sig nificance because it has been identified in 2.3% (103/4400) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs62001050). -

Hermansky-Pudlak syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	3.9
Dann	Benign	0.81
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.44	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.90	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0030	B;.
Vest4		0.22
MVP		0.38
MPC		0.13
ClinPred		0.0019	T
GERP RS		-1.9
Varity_R		0.035
gMVP		0.089

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: rs62001050; hg19: chr5-77406104;