rs17192146

Variant names:

• chr5-78129275-G-A
• rs17192146
• NM_003664.5:c.1683C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003664.5(AP3B1):​c.1683C>T​(p.Leu561Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,612,396 control chromosomes in the GnomAD database, including 3,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (269 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3420 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.97
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-78129275-G-A is Benign according to our data. Variant chr5-78129275-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

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.1683C>T	p.Leu561Leu	synonymous	Exon 16 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1536C>T	p.Leu512Leu	synonymous	Exon 16 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.1683C>T	p.Leu561Leu	synonymous	Exon 16 of 23	NP_001397681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1683C>T	p.Leu561Leu	synonymous	Exon 16 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.1536C>T	p.Leu512Leu	synonymous	Exon 16 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.1683C>T	p.Leu561Leu	synonymous	Exon 16 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7085 AN: 151958 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0605

GnomAD2 exomes AF: 0.0524 AC: 13173 AN: 251214 AF XY: 0.0548

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0802

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0649 AC: 94767 AN: 1460320 Hom.: 3420 Cov.: 34 AF XY: 0.0651 AC XY: 47296 AN XY: 726520

African (AFR) AF: 0.0106 AC: 355 AN: 33454

American (AMR) AF: 0.0374 AC: 1672 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 2124 AN: 26110

East Asian (EAS) AF: 0.000656 AC: 26 AN: 39632

South Asian (SAS) AF: 0.0537 AC: 4634 AN: 86216

European-Finnish (FIN) AF: 0.0385 AC: 2057 AN: 53366

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5760

European-Non Finnish (NFE) AF: 0.0721 AC: 80039 AN: 1110736

Other (OTH) AF: 0.0600 AC: 3618 AN: 60336

GnomAD4 genome AF: 0.0466 AC: 7081 AN: 152076 Hom.: 269 Cov.: 32 AF XY: 0.0451 AC XY: 3351 AN XY: 74352

African (AFR) AF: 0.0118 AC: 489 AN: 41524

American (AMR) AF: 0.0511 AC: 781 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 256 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0539 AC: 260 AN: 4820

European-Finnish (FIN) AF: 0.0292 AC: 309 AN: 10576

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4816 AN: 67928

Other (OTH) AF: 0.0594 AC: 125 AN: 2104

Alfa AF: 0.0628 Hom.: 251

Bravo AF: 0.0479

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0708

EpiControl AF: 0.0707

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.73
PhyloP100		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17192146; hg19: chr5-77425099;