rs763619135

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_003664.5(AP3B1):ā€‹c.2018A>Gā€‹(p.Lys673Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000026 ( 0 hom. )

Consequence

AP3B1
NM_003664.5 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.73
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.077524066).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000131 (2/152206) while in subpopulation AMR AF= 0.000131 (2/15274). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AP3B1NM_003664.5 linkuse as main transcriptc.2018A>G p.Lys673Arg missense_variant 18/27 ENST00000255194.11 NP_003655.3 O00203-1A0A0S2Z5J4
AP3B1NM_001271769.2 linkuse as main transcriptc.1871A>G p.Lys624Arg missense_variant 18/27 NP_001258698.1 O00203-3A0A0S2Z5J4
AP3B1NM_001410752.1 linkuse as main transcriptc.2018A>G p.Lys673Arg missense_variant 18/23 NP_001397681.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AP3B1ENST00000255194.11 linkuse as main transcriptc.2018A>G p.Lys673Arg missense_variant 18/271 NM_003664.5 ENSP00000255194.7 O00203-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000115
AC:
29
AN:
251316
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000752
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461568
Hom.:
0
Cov.:
29
AF XY:
0.0000275
AC XY:
20
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
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
Bravo
AF:
0.0000604
ExAC
AF:
0.000123
AC:
15

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 30, 2024The c.2018A>G (p.K673R) alteration is located in exon 18 (coding exon 18) of the AP3B1 gene. This alteration results from a A to G substitution at nucleotide position 2018, causing the lysine (K) at amino acid position 673 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hermansky-Pudlak syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 27, 2022This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 673 of the AP3B1 protein (p.Lys673Arg). This variant is present in population databases (rs763619135, gnomAD 0.08%). 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: 570217). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;.
Eigen
Benign
0.11
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.078
T;T
MetaSVM
Uncertain
-0.014
T
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.31
Sift
Uncertain
0.024
D;D
Sift4G
Benign
0.13
T;T
Polyphen
0.052
B;.
Vest4
0.15
MutPred
0.27
Loss of methylation at K673 (P = 0.001);.;
MVP
0.72
MPC
0.039
ClinPred
0.13
T
GERP RS
6.0
Varity_R
0.087
gMVP
0.11

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: rs763619135; hg19: chr5-77412009; API