rs112652327

Variant names:

• chr5-78181627-G-A
• rs112652327
• NM_003664.5:c.822C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.822C>T​(p.Tyr274Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,611,960 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.85
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-78181627-G-A is Benign according to our data. Variant chr5-78181627-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 354246.
• BP7: Synonymous conserved (PhyloP=2.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000487 (74/152070) while in subpopulation AFR AF = 0.00147 (61/41480). AF 95% confidence interval is 0.00118. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.822C>T	p.Tyr274Tyr	synonymous	Exon 8 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.675C>T	p.Tyr225Tyr	synonymous	Exon 8 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.822C>T	p.Tyr274Tyr	synonymous	Exon 8 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.822C>T	p.Tyr274Tyr	synonymous	Exon 8 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.675C>T	p.Tyr225Tyr	synonymous	Exon 8 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.822C>T	p.Tyr274Tyr	synonymous	Exon 8 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000329 AC: 82 AN: 249460 AF XY: 0.000252

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1459890 Hom.: 2 Cov.: 31 AF XY: 0.000143 AC XY: 104 AN XY: 726204

African (AFR) AF: 0.00246 AC: 82 AN: 33372

American (AMR) AF: 0.00148 AC: 66 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39578

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52936

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111352

Other (OTH) AF: 0.000730 AC: 44 AN: 60304

GnomAD4 genome AF: 0.000487 AC: 74 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74356

African (AFR) AF: 0.00147 AC: 61 AN: 41480

American (AMR) AF: 0.000590 AC: 9 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000654

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.41
PhyloP100		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs112652327; hg19: chr5-77477451;