chr5-78175810-T-C

Position:

• chr5-78175810-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003664.5(AP3B1):​c.1069A>G​(p.Ile357Val) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,612,266 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: AP3B1 NM_003664.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 5.90

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029283196).
• BP6: Variant 5-78175810-T-C is Benign according to our data. Variant chr5-78175810-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 354243.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr5-78175810-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (267/152326) while in subpopulation NFE AF= 0.00284 (193/68006). AF 95% confidence interval is 0.00251. There are 1 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B1	NM_003664.5	c.1069A>G	p.Ile357Val	missense_variant	10/27	ENST00000255194.11	NP_003655.3
AP3B1	NM_001271769.2	c.922A>G	p.Ile308Val	missense_variant	10/27		NP_001258698.1
AP3B1	NM_001410752.1	c.1069A>G	p.Ile357Val	missense_variant	10/23		NP_001397681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11	c.1069A>G	p.Ile357Val	missense_variant	10/27	1	NM_003664.5	ENSP00000255194.7

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00168 AC: 421 AN: 251064 Hom.: 1 AF XY: 0.00166 AC XY: 225 AN XY: 135704

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00186 AC: 2718 AN: 1459940 Hom.: 9 Cov.: 30 AF XY: 0.00183 AC XY: 1332 AN XY: 726364

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00506

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00298

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74504

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00124

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00148 AC: 180

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Feb 01, 2019	- -

Hermansky-Pudlak syndrome 2 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 23, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.3% [193/68014], including 1 homozygote; https://gnomad.broadinstitute.org/variant/5-78175810-T-C?dataset=gnomad_r3). Evoluationary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2022	Variant summary: AP3B1 c.1069A>G (p.Ile357Val) results in a conservative amino acid change located in the Clathrin/coatomer adaptor, adaptin-like, N-terminal domain (IPR002553) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251064 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1069A>G in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

AP3B1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.12
Sift	Benign	0.22	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.38	B;.
Vest4		0.86
MVP		0.21
MPC		0.083
ClinPred		0.046	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.38

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: rs142025324; hg19: chr5-77471634; COSMIC: COSV99671933;