rs42360

Variant names:

• chr5-78116187-A-G
• rs42360
• NM_003664.5:c.2016T>C

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.2016T>C​(p.Ala672Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,612,438 control chromosomes in the GnomAD database, including 44,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4353 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40268 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.738
• Publications: 19 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=-0.46).
• BP6: Variant 5-78116187-A-G is Benign according to our data. Variant chr5-78116187-A-G is described in ClinVar as Benign. ClinVar VariationId is 162752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.738 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.303 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.2016T>C	p.Ala672Ala	synonymous	Exon 18 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1869T>C	p.Ala623Ala	synonymous	Exon 18 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.2016T>C	p.Ala672Ala	synonymous	Exon 18 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.2016T>C	p.Ala672Ala	synonymous	Exon 18 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.1869T>C	p.Ala623Ala	synonymous	Exon 18 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.2016T>C	p.Ala672Ala	synonymous	Exon 18 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35496 AN: 152032 Hom.: 4349 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0703

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.213 AC: 53518 AN: 251274 AF XY: 0.205

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.229 AC: 334316 AN: 1460288 Hom.: 40268 Cov.: 32 AF XY: 0.225 AC XY: 163524 AN XY: 726512

African (AFR) AF: 0.261 AC: 8720 AN: 33440

American (AMR) AF: 0.311 AC: 13894 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4742 AN: 26110

East Asian (EAS) AF: 0.0758 AC: 3006 AN: 39638

South Asian (SAS) AF: 0.128 AC: 11058 AN: 86238

European-Finnish (FIN) AF: 0.179 AC: 9531 AN: 53356

Middle Eastern (MID) AF: 0.136 AC: 784 AN: 5762

European-Non Finnish (NFE) AF: 0.243 AC: 269554 AN: 1110690

Other (OTH) AF: 0.216 AC: 13027 AN: 60336

GnomAD4 genome AF: 0.234 AC: 35534 AN: 152150 Hom.: 4353 Cov.: 32 AF XY: 0.229 AC XY: 17064 AN XY: 74394

African (AFR) AF: 0.256 AC: 10607 AN: 41500

American (AMR) AF: 0.310 AC: 4733 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3466

East Asian (EAS) AF: 0.0697 AC: 361 AN: 5182

South Asian (SAS) AF: 0.132 AC: 635 AN: 4828

European-Finnish (FIN) AF: 0.169 AC: 1788 AN: 10602

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16151 AN: 67990

Other (OTH) AF: 0.234 AC: 494 AN: 2114

Alfa AF: 0.234 Hom.: 8072

Bravo AF: 0.244

Asia WGS AF: 0.145 AC: 506 AN: 3474

EpiCase AF: 0.232

EpiControl AF: 0.233

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	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	-0.46
CADD	Benign	6.3
DANN	Benign	0.71
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

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: rs42360; hg19: chr5-77412011; COSMIC: COSV54879541; COSMIC: COSV54879541;