5-78002861-T-C

Variant names:

• chr5-78002861-T-C
• rs112214336
• NM_003664.5:c.*41A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003664.5(AP3B1):​c.*41A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0115 in 1,613,294 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (128 hom.)
• Consequence: AP3B1 NM_003664.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.85
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-78002861-T-C is Benign according to our data. Variant chr5-78002861-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1207984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00886 (1349/152322) while in subpopulation NFE AF = 0.0126 (855/68038). AF 95% confidence interval is 0.0119. There are 14 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.*41A>G		3_prime_UTR_variant	Exon 27 of 27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.*41A>G		3_prime_UTR_variant	Exon 27 of 27		NP_001258698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.*41A>G		3_prime_UTR_variant	Exon 27 of 27	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1349 AN: 152204 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00905 AC: 2275 AN: 251436 AF XY: 0.00896

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0118 AC: 17248 AN: 1460972 Hom.: 128 Cov.: 31 AF XY: 0.0116 AC XY: 8449 AN XY: 726864

African (AFR) AF: 0.00227 AC: 76 AN: 33456

American (AMR) AF: 0.00986 AC: 441 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 574 AN: 26134

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

South Asian (SAS) AF: 0.00486 AC: 419 AN: 86240

European-Finnish (FIN) AF: 0.00586 AC: 313 AN: 53418

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5764

European-Non Finnish (NFE) AF: 0.0132 AC: 14696 AN: 1111186

Other (OTH) AF: 0.0115 AC: 693 AN: 60364

GnomAD4 genome AF: 0.00886 AC: 1349 AN: 152322 Hom.: 14 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74486

African (AFR) AF: 0.00303 AC: 126 AN: 41562

American (AMR) AF: 0.0118 AC: 180 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 855 AN: 68038

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0104 Hom.: 8

Bravo AF: 0.00990

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		3.8
Mutation Taster		=100/0	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: rs112214336; hg19: chr5-77298685; COSMIC: COSV54876708; COSMIC: COSV54876708;