rs4532349

Variant names:

• chr5-78177341-A-G
• rs4532349
• NM_003664.5:c.1038T>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.1038T>C​(p.Asn346Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,604,018 control chromosomes in the GnomAD database, including 38,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2847 hom., cov: 32)
  • Exomes 𝑓: 0.21 (35352 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.001395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 3.11
• 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=-0.36).
• BP6: Variant 5-78177341-A-G is Benign according to our data. Variant chr5-78177341-A-G is described in ClinVar as Benign. ClinVar VariationId is 178705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.264 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.1038T>C	p.Asn346Asn	splice_region synonymous	Exon 9 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.891T>C	p.Asn297Asn	splice_region synonymous	Exon 9 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.1038T>C	p.Asn346Asn	splice_region synonymous	Exon 9 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.1038T>C	p.Asn346Asn	splice_region synonymous	Exon 9 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.891T>C	p.Asn297Asn	splice_region synonymous	Exon 9 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.1038T>C	p.Asn346Asn	splice_region synonymous	Exon 9 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27948 AN: 152022 Hom.: 2843 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0694

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.194 AC: 48604 AN: 251172 AF XY: 0.188

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.0598

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.214 AC: 310203 AN: 1451880 Hom.: 35352 Cov.: 29 AF XY: 0.211 AC XY: 152200 AN XY: 722954

African (AFR) AF: 0.103 AC: 3446 AN: 33334

American (AMR) AF: 0.293 AC: 13076 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4520 AN: 26058

East Asian (EAS) AF: 0.0748 AC: 2964 AN: 39612

South Asian (SAS) AF: 0.120 AC: 10292 AN: 86008

European-Finnish (FIN) AF: 0.175 AC: 9319 AN: 53386

Middle Eastern (MID) AF: 0.120 AC: 691 AN: 5748

European-Non Finnish (NFE) AF: 0.230 AC: 254138 AN: 1102966

Other (OTH) AF: 0.196 AC: 11757 AN: 60086

GnomAD4 genome AF: 0.184 AC: 27972 AN: 152138 Hom.: 2847 Cov.: 32 AF XY: 0.182 AC XY: 13499 AN XY: 74374

African (AFR) AF: 0.115 AC: 4783 AN: 41516

American (AMR) AF: 0.271 AC: 4134 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3466

East Asian (EAS) AF: 0.0688 AC: 357 AN: 5188

South Asian (SAS) AF: 0.125 AC: 603 AN: 4824

European-Finnish (FIN) AF: 0.165 AC: 1743 AN: 10582

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15232 AN: 67978

Other (OTH) AF: 0.187 AC: 396 AN: 2114

Alfa AF: 0.210 Hom.: 5495

Bravo AF: 0.187

Asia WGS AF: 0.126 AC: 438 AN: 3478

EpiCase AF: 0.217

EpiControl AF: 0.219

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	-0.36
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=48/52	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.010
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: rs4532349; hg19: chr5-77473165; COSMIC: COSV54880120;