rs139344924

Variant names:

• chr5-78039191-G-T
• rs139344924
• NM_003664.5:c.2661C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003664.5(AP3B1):​c.2661C>A​(p.Phe887Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,086 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.63
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114659965).
• BP6: Variant 5-78039191-G-T is Benign according to our data. Variant chr5-78039191-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210189.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00694 (1056/152260) while in subpopulation SAS AF = 0.0137 (66/4828). AF 95% confidence interval is 0.0111. There are 5 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2661C>A	p.Phe887Leu	missense	Exon 23 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.2514C>A	p.Phe838Leu	missense	Exon 23 of 27	NP_001258698.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2661C>A	p.Phe887Leu	missense	Exon 23 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.2514C>A	p.Phe838Leu	missense	Exon 23 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.2661C>A	p.Phe887Leu	missense	Exon 23 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152142 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00774 AC: 1947 AN: 251458 AF XY: 0.00819

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0105 AC: 15376 AN: 1461826 Hom.: 105 Cov.: 32 AF XY: 0.0105 AC XY: 7618 AN XY: 727214

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00369 AC: 165 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0128 AC: 1100 AN: 86258

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53416

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13054 AN: 1111972

Other (OTH) AF: 0.0125 AC: 757 AN: 60392

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152260 Hom.: 5 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74444

African (AFR) AF: 0.00195 AC: 81 AN: 41570

American (AMR) AF: 0.00412 AC: 63 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4828

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 798 AN: 68002

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00945 Hom.: 19

Bravo AF: 0.00636

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00784 AC: 952

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00865

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hermansky-Pudlak syndrome 2 (2)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.059
Sift	Benign	0.65	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.37		Gain of sheet (P = 0.0827)
MVP		0.28
MPC		0.068
ClinPred		0.013	T
GERP RS		5.8
PromoterAI		-0.036	Neutral
Varity_R		0.10
gMVP		0.58
Mutation Taster		=93/7	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: rs139344924; hg19: chr5-77335015; COSMIC: COSV106092631; COSMIC: COSV106092631;