4-6716337-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018366.3(BLOC1S4):​c.128C>T​(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000404 in 1,236,220 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

BLOC1S4
NM_018366.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57
Variant links:
Genes affected
BLOC1S4 (HGNC:24206): (biogenesis of lysosomal organelles complex 1 subunit 4) This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and is a model for Hermansky-Pudlak syndrome. The encoded protein may play a role in intracellular vesicular trafficking. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05411756).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLOC1S4NM_018366.3 linkc.128C>T p.Pro43Leu missense_variant Exon 1 of 1 ENST00000320776.5 NP_060836.1 Q9NUP1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLOC1S4ENST00000320776.5 linkc.128C>T p.Pro43Leu missense_variant Exon 1 of 1 6 NM_018366.3 ENSP00000318128.3 Q9NUP1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151668
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
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:
0.000479
GnomAD4 exome
AF:
0.00000277
AC:
3
AN:
1084552
Hom.:
0
Cov.:
31
AF XY:
0.00000389
AC XY:
2
AN XY:
513764
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000685
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151668
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74046
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
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:
0.000479
Bravo
AF:
0.0000264

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.128C>T (p.P43L) alteration is located in exon 1 (coding exon 1) of the BLOC1S4 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.072
T
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.054
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.49
N
REVEL
Benign
0.023
Sift
Benign
0.38
T
Sift4G
Benign
0.36
T
Polyphen
0.012
B
Vest4
0.068
MutPred
0.14
Loss of glycosylation at P43 (P = 0.115);
MVP
0.26
MPC
0.77
ClinPred
0.19
T
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.050
gMVP
0.19

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: rs1714898100; hg19: chr4-6718064; API