rs76433453

Variant names:

• chr5-78175677-C-G
• rs76433453
• NM_003664.5:c.1116G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-78175677-C-G
• chr5-78175677-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003664.5(AP3B1):​c.1116G>C​(p.Leu372Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,613,356 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (145 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (148 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.95
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 5-78175677-C-G is Benign according to our data. Variant chr5-78175677-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

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.1116G>C	p.Leu372Leu	synonymous	Exon 11 of 27	NP_003655.3
	AP3B1	NM_001271769.2		c.969G>C	p.Leu323Leu	synonymous	Exon 11 of 27	NP_001258698.1	O00203-3
	AP3B1	NM_001410752.1		c.1116G>C	p.Leu372Leu	synonymous	Exon 11 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.1116G>C	p.Leu372Leu	synonymous	Exon 11 of 27	ENSP00000255194.7	O00203-1
	AP3B1	ENST00000519295.7	TSL:1	c.969G>C	p.Leu323Leu	synonymous	Exon 11 of 27	ENSP00000430597.1	O00203-3
	AP3B1	ENST00000913629.1		c.1116G>C	p.Leu372Leu	synonymous	Exon 11 of 27	ENSP00000583688.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3461 AN: 152130 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00634 AC: 1590 AN: 250814 AF XY: 0.00459

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00265 AC: 3876 AN: 1461108 Hom.: 148 Cov.: 30 AF XY: 0.00238 AC XY: 1728 AN XY: 726932

African (AFR) AF: 0.0858 AC: 2867 AN: 33426

American (AMR) AF: 0.00617 AC: 276 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5760

European-Non Finnish (NFE) AF: 0.000289 AC: 321 AN: 1111560

Other (OTH) AF: 0.00590 AC: 356 AN: 60358

GnomAD4 genome AF: 0.0227 AC: 3463 AN: 152248 Hom.: 145 Cov.: 32 AF XY: 0.0224 AC XY: 1670 AN XY: 74438

African (AFR) AF: 0.0762 AC: 3165 AN: 41528

American (AMR) AF: 0.0147 AC: 225 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68012

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.00717 Hom.: 14

Bravo AF: 0.0272

Asia WGS AF: 0.00434 AC: 15 AN: 3474

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.7
DANN	Benign	0.79
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

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: rs76433453; hg19: chr5-77471501;