rs75248449

Variant names:

• chr5-78162865-A-C
• rs75248449
• NM_003664.5:c.1317T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.1317T>G​(p.Thr439Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,614,064 control chromosomes in the GnomAD database, including 32 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 0.0052 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (32 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.928
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-78162865-A-C is Benign according to our data. Variant chr5-78162865-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178704.
• BP7: Synonymous conserved (PhyloP=-0.928 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00516 (786/152342) while in subpopulation AMR AF = 0.0123 (189/15310). AF 95% confidence interval is 0.0109. There are 0 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 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.1317T>G	p.Thr439Thr	synonymous	Exon 13 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1170T>G	p.Thr390Thr	synonymous	Exon 13 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.1317T>G	p.Thr439Thr	synonymous	Exon 13 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.1317T>G	p.Thr439Thr	synonymous	Exon 13 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.1170T>G	p.Thr390Thr	synonymous	Exon 13 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.1317T>G	p.Thr439Thr	synonymous	Exon 13 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 787 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00460 AC: 1156 AN: 251326 AF XY: 0.00451

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00553 AC: 8082 AN: 1461722 Hom.: 32 Cov.: 31 AF XY: 0.00538 AC XY: 3911 AN XY: 727166

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.00521 AC: 233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 311 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86254

European-Finnish (FIN) AF: 0.00579 AC: 309 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00603 AC: 6709 AN: 1111876

Other (OTH) AF: 0.00563 AC: 340 AN: 60390

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00509 AC XY: 379 AN XY: 74496

African (AFR) AF: 0.00127 AC: 53 AN: 41588

American (AMR) AF: 0.0123 AC: 189 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68022

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00527 Hom.: 2

Bravo AF: 0.00514

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autoinflammatory syndrome (1)
-	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	-0.85
CADD	Benign	0.28
DANN	Benign	0.37
PhyloP100		-0.93
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: rs75248449; hg19: chr5-77458689;