12-55716088-C-T

Variant summary

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

The NM_001487.4(BLOC1S1):​c.37C>T​(p.Arg13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000631 in 1,583,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 32)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

BLOC1S1
NM_001487.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.69
Variant links:
Genes affected
BLOC1S1 (HGNC:4200): (biogenesis of lysosomal organelles complex 1 subunit 1) BLOC1S1 is a component of the ubiquitously expressed BLOC1 multisubunit protein complex. BLOC1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (Starcevic and Dell'Angelica, 2004 [PubMed 15102850]).[supplied by OMIM, Mar 2008]
ITGA7 (HGNC:6143): (integrin subunit alpha 7) The protein encoded by this gene belongs to the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. They mediate a wide spectrum of cell-cell and cell-matrix interactions, and thus play a role in cell migration, morphologic development, differentiation, and metastasis. This protein functions as a receptor for the basement membrane protein laminin-1. It is mainly expressed in skeletal and cardiac muscles and may be involved in differentiation and migration processes during myogenesis. Defects in this gene are associated with congenital myopathy. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2009]

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=0.04485908).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BLOC1S1NM_001487.4 linkc.37C>T p.Arg13Trp missense_variant Exon 1 of 4 ENST00000548925.6 NP_001478.2 P78537-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BLOC1S1ENST00000548925.6 linkc.37C>T p.Arg13Trp missense_variant Exon 1 of 4 1 NM_001487.4 ENSP00000447537.1 P78537-1
ENSG00000258311ENST00000550412.5 linkc.37C>T p.Arg13Trp missense_variant Exon 1 of 4 2 ENSP00000447650.1 F8W036

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152106
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:
0.0000201
AC:
4
AN:
198856
Hom.:
0
AF XY:
0.0000279
AC XY:
3
AN XY:
107462
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000104
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:
0.0000117
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000559
AC:
8
AN:
1431664
Hom.:
0
Cov.:
30
AF XY:
0.00000845
AC XY:
6
AN XY:
709982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000101
Gnomad4 ASJ exome
AF:
0.0000391
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000242
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.11e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74436
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:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.37C>T (p.R13W) alteration is located in exon 1 (coding exon 1) of the BLOC1S1 gene. This alteration results from a C to T substitution at nucleotide position 37, causing the arginine (R) at amino acid position 13 to be replaced by a tryptophan (W). 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
0.19
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
12
DANN
Benign
0.93
DEOGEN2
Benign
0.059
.;T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.66
T;T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.045
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;N;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.18
N;N;N
REVEL
Uncertain
0.34
Sift
Uncertain
0.023
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.0
B;.;B
Vest4
0.24
MutPred
0.23
Loss of methylation at R13 (P = 0.0137);Loss of methylation at R13 (P = 0.0137);Loss of methylation at R13 (P = 0.0137);
MVP
0.16
MPC
0.023
ClinPred
0.20
T
GERP RS
-6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.089
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs533860678; hg19: chr12-56109872; API