5-78002858-C-T

Position:

• chr5-78002858-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000255194.11(AP3B1):​c.*44G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00178 in 1,612,760 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: AP3B1 ENST00000255194.11 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-78002858-C-T is Benign according to our data. Variant chr5-78002858-C-T is described in ClinVar as [Benign]. Clinvar id is 906459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00195 (297/152316) while in subpopulation AMR AF= 0.0111 (170/15292). AF 95% confidence interval is 0.00975. There are 1 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.*44G>A		3_prime_UTR_variant	27/27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.*44G>A		3_prime_UTR_variant	27/27		NP_001258698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.*44G>A		3_prime_UTR_variant	27/27	1	NM_003664.5	ENSP00000255194	P2

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00392 AC: 985 AN: 251430 Hom.: 10 AF XY: 0.00325 AC XY: 442 AN XY: 135880

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00412

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00176 AC: 2567 AN: 1460444 Hom.: 20 Cov.: 30 AF XY: 0.00172 AC XY: 1252 AN XY: 726618

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74492

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00295

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs182487478; hg19: chr5-77298682;