chr5-78141213-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_003664.5(AP3B1):​c.1580G>A​(p.Ser527Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S527G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

AP3B1
NM_003664.5 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.298
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.031412035).
BP6
Variant 5-78141213-C-T is Benign according to our data. Variant chr5-78141213-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505163.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AP3B1NM_003664.5 linkc.1580G>A p.Ser527Asn missense_variant Exon 15 of 27 ENST00000255194.11 NP_003655.3 O00203-1A0A0S2Z5J4
AP3B1NM_001271769.2 linkc.1433G>A p.Ser478Asn missense_variant Exon 15 of 27 NP_001258698.1 O00203-3A0A0S2Z5J4
AP3B1NM_001410752.1 linkc.1580G>A p.Ser527Asn missense_variant Exon 15 of 23 NP_001397681.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AP3B1ENST00000255194.11 linkc.1580G>A p.Ser527Asn missense_variant Exon 15 of 27 1 NM_003664.5 ENSP00000255194.7 O00203-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152202
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251228
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135788
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461550
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727070
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74360
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 2 Uncertain:1
Oct 19, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with AP3B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505163). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 527 of the AP3B1 protein (p.Ser527Asn). -

not specified Benign:1
Jul 13, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ser527Asn in exon 15 of AP3B1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 6 mammals have an asparagine (Asn) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugges t a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
5.4
DANN
Benign
0.84
DEOGEN2
Benign
0.15
T;.
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.069
N
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.031
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
-0.28
N;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
0.49
N;N
REVEL
Benign
0.093
Sift
Benign
0.80
T;T
Sift4G
Benign
0.70
T;T
Polyphen
0.018
B;.
Vest4
0.080
MutPred
0.43
Loss of disorder (P = 0.084);.;
MVP
0.18
MPC
0.043
ClinPred
0.16
T
GERP RS
3.1
Varity_R
0.028
gMVP
0.16

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.

Other links and lift over

dbSNP: rs779511911; hg19: chr5-77437037; API