rs115340604

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	NM_003664.5	MANE Select	c.2810-4C>T		splice_region intron	N/A	NP_003655.3
	AP3B1	NM_001271769.2		c.2663-4C>T		splice_region intron	N/A	NP_001258698.1	O00203-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.2810-4C>T		splice_region intron	N/A	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.2663-4C>T		splice_region intron	N/A	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.2810-4C>T		splice_region intron	N/A	ENSP00000583688.1

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hermansky-Pudlak syndrome 2 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;