rs142938290

Variant names:

• chr5-78110294-G-A
• rs142938290
• NM_003664.5:c.2310C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_003664.5(AP3B1):​c.2310C>T​(p.Asp770Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,607,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.487
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-78110294-G-A is Benign according to our data. Variant chr5-78110294-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464883.
• BP7: Synonymous conserved (PhyloP=-0.487 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00025 (38/152160) while in subpopulation SAS AF = 0.000415 (2/4824). AF 95% confidence interval is 0.000255. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.2310C>T	p.Asp770Asp	synonymous	Exon 20 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2163C>T	p.Asp721Asp	synonymous	Exon 20 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.2310C>T	p.Asp770Asp	synonymous	Exon 20 of 23	NP_001397681.1	A0A8Q3SIM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2310C>T	p.Asp770Asp	synonymous	Exon 20 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.2163C>T	p.Asp721Asp	synonymous	Exon 20 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.2310C>T	p.Asp770Asp	synonymous	Exon 20 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000224 AC: 55 AN: 245020 AF XY: 0.000227

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000279 AC: 406 AN: 1454926 Hom.: 0 Cov.: 29 AF XY: 0.000283 AC XY: 205 AN XY: 723616

African (AFR) AF: 0.0000899 AC: 3 AN: 33370

American (AMR) AF: 0.000180 AC: 8 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39564

South Asian (SAS) AF: 0.000304 AC: 26 AN: 85600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.000316 AC: 350 AN: 1107010

Other (OTH) AF: 0.000283 AC: 17 AN: 60092

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74366

African (AFR) AF: 0.000169 AC: 7 AN: 41518

American (AMR) AF: 0.000262 AC: 4 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.000234

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hermansky-Pudlak syndrome 2 (2)
-	-	1	AP3B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.1
DANN	Benign	0.82
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142938290; hg19: chr5-77406118;