5-78039122-A-G

Position:

• chr5-78039122-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003664.5(AP3B1):​c.2730T>C​(p.Thr910=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,613,746 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (30 hom.)
• Consequence: AP3B1 NM_003664.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.754

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-78039122-A-G is Benign according to our data. Variant chr5-78039122-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 286838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78039122-A-G is described in Lovd as [Benign]. Variant chr5-78039122-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00271 (412/152276) while in subpopulation NFE AF= 0.00498 (339/68016). AF 95% confidence interval is 0.00455. There are 1 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.2730T>C	p.Thr910=	synonymous_variant	23/27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.2583T>C	p.Thr861=	synonymous_variant	23/27		NP_001258698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.2730T>C	p.Thr910=	synonymous_variant	23/27	1	NM_003664.5	ENSP00000255194	P2

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00498

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00207 AC: 520 AN: 251324 Hom.: 2 AF XY: 0.00211 AC XY: 286 AN XY: 135834

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00479 AC: 6994 AN: 1461470 Hom.: 30 Cov.: 31 AF XY: 0.00462 AC XY: 3357 AN XY: 727050

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00561

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74460

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00498

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 13, 2018	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	AP3B1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2021	- -

Hermansky-Pudlak syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.6
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs143527588; hg19: chr5-77334946;