rs113301033

Variant names:

• chr5-78116161-T-C
• rs113301033
• NM_003664.5:c.2042A>G

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.2042A>G​(p.Glu681Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000736 in 1,613,844 control chromosomes in the GnomAD database, including 8 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 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (6 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.46
• Publications: 2 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=0.006723702).
• BP6: Variant 5-78116161-T-C is Benign according to our data. Variant chr5-78116161-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235303.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00366 (557/152338) while in subpopulation AFR AF = 0.0125 (518/41578). AF 95% confidence interval is 0.0116. There are 2 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.2042A>G	p.Glu681Gly	missense	Exon 18 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1895A>G	p.Glu632Gly	missense	Exon 18 of 27	NP_001258698.1
	AP3B1	NM_001410752.1		c.2042A>G	p.Glu681Gly	missense	Exon 18 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.2042A>G	p.Glu681Gly	missense	Exon 18 of 27	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.1895A>G	p.Glu632Gly	missense	Exon 18 of 27	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.2042A>G	p.Glu681Gly	missense	Exon 18 of 26	ENSP00000511978.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00107 AC: 268 AN: 251324 AF XY: 0.000825

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000432 AC: 631 AN: 1461506 Hom.: 6 Cov.: 29 AF XY: 0.000389 AC XY: 283 AN XY: 727086

African (AFR) AF: 0.0152 AC: 510 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111788

Other (OTH) AF: 0.00147 AC: 89 AN: 60382

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00369 AC XY: 275 AN XY: 74500

African (AFR) AF: 0.0125 AC: 518 AN: 41578

American (AMR) AF: 0.00176 AC: 27 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00403

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.30	T
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.41
MVP		0.42
MPC		0.12
ClinPred		0.018	T
GERP RS		5.3
Varity_R		0.12
gMVP		0.22
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: rs113301033; hg19: chr5-77411985;