rs5868908

Variant names:

• chr5-78228244-TA-T
• rs5868908
• NM_003664.5:c.280-6delT

Your query was ambiguous. Multiple possible variants found:

• chr5-78228244-TA-T
• chr5-78228244-TA-TAA
• chr5-78228244-TA-TAAA
• chr5-78228244-TA-TAAAA
• chr5-78228244-TA-TAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_003664.5(AP3B1):​c.280-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,558,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10
• Publications: 6 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 5-78228244-TA-T is Benign according to our data. Variant chr5-78228244-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1167500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000528 (8/151522) while in subpopulation EAS AF = 0.000578 (3/5192). AF 95% confidence interval is 0.000157. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.280-6delT		splice_region_variant, intron_variant	Intron 3 of 26	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.133-6delT		splice_region_variant, intron_variant	Intron 3 of 26		NP_001258698.1
AP3B1	NM_001410752.1	c.280-6delT		splice_region_variant, intron_variant	Intron 3 of 22		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.280-6delT		splice_region_variant, intron_variant	Intron 3 of 26	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000210 AC: 47 AN: 223498 AF XY: 0.000206

Gnomad AFR exome AF: 0.0000694

Gnomad AMR exome AF: 0.000454

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.000309

Gnomad FIN exome AF: 0.000348

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.000134 AC: 188 AN: 1407146 Hom.: 0 Cov.: 26 AF XY: 0.000123 AC XY: 86 AN XY: 701126

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

African (AFR) AF: 0.000188 AC: 6 AN: 31972

American (AMR) AF: 0.000209 AC: 9 AN: 43152

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25058

East Asian (EAS) AF: 0.000261 AC: 10 AN: 38346

South Asian (SAS) AF: 0.000120 AC: 10 AN: 83076

European-Finnish (FIN) AF: 0.000206 AC: 10 AN: 48588

Middle Eastern (MID) AF: 0.000357 AC: 2 AN: 5610

European-Non Finnish (NFE) AF: 0.000123 AC: 132 AN: 1073066

Other (OTH) AF: 0.000137 AC: 8 AN: 58278

⚠️ 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 AF: 0.0000528 AC: 8 AN: 151522 Hom.: 0 Cov.: 0 AF XY: 0.0000676 AC XY: 5 AN XY: 73954

African (AFR) AF: 0.00 AC: 0 AN: 41184

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

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

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000954 Hom.: 761

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

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: rs5868908; hg19: chr5-77524068; COSMIC: COSV54885282;