chr5-78228244-T-TAAA

Variant names:

• chr5-78228244-T-TAAA
• rs5868908
• NM_003664.5:c.280-8_280-6dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003664.5(AP3B1):​c.280-8_280-6dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,552 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.280-8_280-6dupTTT		splice_region intron	N/A	NP_003655.3
	AP3B1	NM_001271769.2		c.133-8_133-6dupTTT		splice_region intron	N/A	NP_001258698.1
	AP3B1	NM_001410752.1		c.280-8_280-6dupTTT		splice_region intron	N/A	NP_001397681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.280-6_280-5insTTT		splice_region intron	N/A	ENSP00000255194.7
	AP3B1	ENST00000519295.7	TSL:1	c.133-6_133-5insTTT		splice_region intron	N/A	ENSP00000430597.1
	AP3B1	ENST00000695515.1		c.280-6_280-5insTTT		splice_region intron	N/A	ENSP00000511978.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408552 Hom.: 0 Cov.: 26 AF XY: 0.00000142 AC XY: 1 AN XY: 701826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31994

American (AMR) AF: 0.00 AC: 0 AN: 43232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 38404

South Asian (SAS) AF: 0.00 AC: 0 AN: 83208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074064

Other (OTH) AF: 0.00 AC: 0 AN: 58338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5868908; hg19: chr5-77524068;