5-78165642-C-G

Variant names:

• chr5-78165642-C-G
• rs150000996
• NM_003664.5:c.1198G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_003664.5(AP3B1):​c.1198G>C​(p.Ala400Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,609,360 control chromosomes in the GnomAD database, including 6 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 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2 O:1
• Conservation: PhyloP100: 1.75
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1881237).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000861 (131/152200) while in subpopulation NFE AF = 0.00169 (115/68038). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1198G>C	p.Ala400Pro	missense	Exon 12 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1051G>C	p.Ala351Pro	missense	Exon 12 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.1198G>C	p.Ala400Pro	missense	Exon 12 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.1198G>C	p.Ala400Pro	missense	Exon 12 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.1051G>C	p.Ala351Pro	missense	Exon 12 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.1198G>C	p.Ala400Pro	missense	Exon 12 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000800 AC: 197 AN: 246196 AF XY: 0.000789

Gnomad AFR exome AF: 0.000591

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00199 AC: 2897 AN: 1457160 Hom.: 6 Cov.: 29 AF XY: 0.00191 AC XY: 1383 AN XY: 724708

African (AFR) AF: 0.000359 AC: 12 AN: 33396

American (AMR) AF: 0.0000900 AC: 4 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85764

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00245 AC: 2714 AN: 1108922

Other (OTH) AF: 0.00269 AC: 162 AN: 60234

GnomAD4 genome AF: 0.000861 AC: 131 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000740 AC XY: 55 AN XY: 74350

African (AFR) AF: 0.000338 AC: 14 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68038

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000569 AC: 69

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Hermansky-Pudlak syndrome 2 (5)
-	2	-	not provided (2)
-	1	1	not specified (2)
-	-	1	AP3B1-related disorder (1)
-	1	-	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.057	T
Sift4G	Benign	0.11	T
Polyphen		0.64	P
Vest4		0.72
MVP		0.34
MPC		0.32
ClinPred		0.067	T
GERP RS		4.5
Varity_R		0.59
gMVP		0.71
Mutation Taster		=71/29	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: rs150000996; hg19: chr5-77461466;