chr5-78128141-A-C

Variant names:

• chr5-78128141-A-C
• rs115892142
• NM_003664.5:c.1857T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.1857T>G​(p.Leu619Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,608,940 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.83
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 5-78128141-A-C is Benign according to our data. Variant chr5-78128141-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00191 (291/152264) while in subpopulation NFE AF = 0.0029 (197/67986). AF 95% confidence interval is 0.00257. There are 1 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.1857T>G	p.Leu619Leu	synonymous	Exon 17 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.1710T>G	p.Leu570Leu	synonymous	Exon 17 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.1857T>G	p.Leu619Leu	synonymous	Exon 17 of 23	NP_001397681.1	A0A8Q3SIM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3B1	ENST00000255194.11	TSL:1 MANE Select	c.1857T>G	p.Leu619Leu	synonymous	Exon 17 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.1710T>G	p.Leu570Leu	synonymous	Exon 17 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.1857T>G	p.Leu619Leu	synonymous	Exon 17 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00290

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00213 AC: 534 AN: 251126 AF XY: 0.00224

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00620

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00242 AC: 3529 AN: 1456676 Hom.: 8 Cov.: 30 AF XY: 0.00240 AC XY: 1739 AN XY: 724982

African (AFR) AF: 0.000330 AC: 11 AN: 33324

American (AMR) AF: 0.000246 AC: 11 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000546 AC: 47 AN: 86156

European-Finnish (FIN) AF: 0.00542 AC: 289 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00277 AC: 3072 AN: 1107514

Other (OTH) AF: 0.00163 AC: 98 AN: 60224

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74464

African (AFR) AF: 0.000241 AC: 10 AN: 41566

American (AMR) AF: 0.000981 AC: 15 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 67986

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00148

EpiCase AF: 0.00234

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hermansky-Pudlak syndrome 2 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.5
DANN	Benign	0.85
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115892142; hg19: chr5-77423965;