4-6716567-C-A

Variant summary

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

The NM_018366.3(BLOC1S4):​c.358C>A​(p.Arg120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000594 in 1,583,030 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 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

BLOC1S4
NM_018366.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06
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=0.025052845).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLOC1S4NM_018366.3 linkc.358C>A p.Arg120Ser 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.358C>A p.Arg120Ser missense_variant Exon 1 of 1 6 NM_018366.3 ENSP00000318128.3 Q9NUP1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
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:
0.00186
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000885
AC:
17
AN:
192194
Hom.:
0
AF XY:
0.000104
AC XY:
11
AN XY:
106220
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000679
Gnomad SAS exome
AF:
0.000599
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000594
AC:
85
AN:
1430664
Hom.:
0
Cov.:
31
AF XY:
0.0000704
AC XY:
50
AN XY:
710172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000262
Gnomad4 SAS exome
AF:
0.000925
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.08e-7
Gnomad4 OTH exome
AF:
0.000101
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152366
Hom.:
0
Cov.:
33
AF XY:
0.0000939
AC XY:
7
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00186
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.000100
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 10, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.358C>A (p.R120S) alteration is located in exon 1 (coding exon 1) of the BLOC1S4 gene. This alteration results from a C to A substitution at nucleotide position 358, causing the arginine (R) at amino acid position 120 to be replaced by a serine (S). 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
0.26
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.025
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.073
Sift
Benign
0.080
T
Sift4G
Benign
0.19
T
Polyphen
0.60
P
Vest4
0.25
MVP
0.29
MPC
1.2
ClinPred
0.059
T
GERP RS
1.8
Varity_R
0.14
gMVP
0.40

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: rs536268453; hg19: chr4-6718294; API