rs35496909

Variant names:

• chr5-78216154-T-C
• rs35496909
• NM_003664.5:c.687A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-78216154-T-C
• chr5-78216154-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.687A>G​(p.Leu229Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,056 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (50 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.30
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-78216154-T-C is Benign according to our data. Variant chr5-78216154-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2153/152276) while in subpopulation AFR AF = 0.0491 (2042/41556). AF 95% confidence interval is 0.0474. There are 58 homozygotes in GnomAd4. There are 1050 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.687A>G	p.Leu229Leu	synonymous	Exon 7 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.540A>G	p.Leu180Leu	synonymous	Exon 7 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.687A>G	p.Leu229Leu	synonymous	Exon 7 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.687A>G	p.Leu229Leu	synonymous	Exon 7 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.540A>G	p.Leu180Leu	synonymous	Exon 7 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.687A>G	p.Leu229Leu	synonymous	Exon 7 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2144 AN: 152158 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00383 AC: 962 AN: 251342 AF XY: 0.00284

Gnomad AFR exome AF: 0.0521

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00150 AC: 2195 AN: 1461780 Hom.: 50 Cov.: 32 AF XY: 0.00135 AC XY: 983 AN XY: 727196

African (AFR) AF: 0.0516 AC: 1727 AN: 33478

American (AMR) AF: 0.00224 AC: 100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1111926

Other (OTH) AF: 0.00316 AC: 191 AN: 60390

GnomAD4 genome AF: 0.0141 AC: 2153 AN: 152276 Hom.: 58 Cov.: 32 AF XY: 0.0141 AC XY: 1050 AN XY: 74454

African (AFR) AF: 0.0491 AC: 2042 AN: 41556

American (AMR) AF: 0.00419 AC: 64 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68004

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00816 Hom.: 7

Bravo AF: 0.0164

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.73
DANN	Benign	0.66
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs35496909; hg19: chr5-77511978;