5-78034449-G-A

Variant names:

• chr5-78034449-G-A
• rs115340604
• NM_003664.5:c.2810-4C>T

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.2810-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,601,282 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (17 hom.)
• Consequence: AP3B1 NM_003664.5 splice_region, intron
• Scores: Splicing: ADA: 0.006250
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08
• 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=-0.38).
• BP6: Variant 5-78034449-G-A is Benign according to our data. Variant chr5-78034449-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00936 (1421/151896) while in subpopulation AFR AF = 0.0326 (1354/41480). AF 95% confidence interval is 0.0312. There are 19 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.2810-4C>T		splice_region_variant, intron_variant	Intron 23 of 26	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.2663-4C>T		splice_region_variant, intron_variant	Intron 23 of 26		NP_001258698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.2810-4C>T		splice_region_variant, intron_variant	Intron 23 of 26	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1419 AN: 151778 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00251 AC: 629 AN: 250816 AF XY: 0.00187

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000922 AC: 1337 AN: 1449386 Hom.: 17 Cov.: 27 AF XY: 0.000774 AC XY: 559 AN XY: 721790

African (AFR) AF: 0.0332 AC: 1102 AN: 33186

American (AMR) AF: 0.00179 AC: 80 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5738

European-Non Finnish (NFE) AF: 0.0000254 AC: 28 AN: 1100992

Other (OTH) AF: 0.00187 AC: 112 AN: 59914

GnomAD4 genome AF: 0.00936 AC: 1421 AN: 151896 Hom.: 19 Cov.: 32 AF XY: 0.00897 AC XY: 666 AN XY: 74234

African (AFR) AF: 0.0326 AC: 1354 AN: 41480

American (AMR) AF: 0.00288 AC: 44 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67800

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00576 Hom.: 7

Bravo AF: 0.0110

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Autoinflammatory syndrome Benign:1

Feb 23, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: 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	-0.38
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		2.1
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.010		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: rs115340604; hg19: chr5-77330273;