chr5-78020769-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_003664.5(AP3B1):c.2915A>G(p.Asn972Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,612,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: -2.37

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007375002).

BP6

Variant 5-78020769-T-C is Benign according to our data. Variant chr5-78020769-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=3}. Variant chr5-78020769-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (295/152252) while in subpopulation AFR AF= 0.00609 (253/41564). AF 95% confidence interval is 0.00547. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B1	NM_003664.5 link	c.2915A>G	p.Asn972Ser	missense_variant	Exon 25 of 27	ENST00000255194.11	NP_003655.3	O00203-1A0A0S2Z5J4
AP3B1	NM_001271769.2 link	c.2768A>G	p.Asn923Ser	missense_variant	Exon 25 of 27		NP_001258698.1	O00203-3A0A0S2Z5J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B1	ENST00000255194.11 link	c.2915A>G	p.Asn972Ser	missense_variant	Exon 25 of 27	1	NM_003664.5	ENSP00000255194.7		O00203-1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.000818

AC:

205

AN:

250490

Hom.:

AF XY:

0.000628

AC XY:

AN XY:

135446

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000336

AC:

491

AN:

1459950

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

212

AN XY:

726354

show subpopulations

Gnomad4 AFR exome

AF:

0.00628

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152252

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00609

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.000335

Hom.:

Bravo

AF:

0.00230

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 2

Uncertain:1Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP3B1 NM_003664.4 exon 25 p.Asn972Ser (c.2915A>G): This variant has not been reported in the literature but is present in 0.6% (163/24026) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs139968311). This variant is present in ClinVar (Variation ID:464884). This variant amino acid Serine (Ser) is present in >40 species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Uncertain:1Benign:1

Apr 11, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP3B1: BP4, BS1 -

Hermansky-Pudlak syndrome

Uncertain:1

Oct 02, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

May 31, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 12, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

AP3B1-related disorder

Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 29, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.035

DANN

Benign

0.45

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.096

Sift

Benign

0.83

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.0

B;.

Vest4

0.12

MVP

0.28

MPC

0.037

ClinPred

0.0011

GERP RS

-8.2

Varity_R

0.024

gMVP

0.037

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over