10-100280150-T-A

Variant names:

• chr10-100280150-T-A
• NM_173809.5:c.371A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173809.5(BLOC1S2):​c.371A>T​(p.Lys124Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BLOC1S2 NM_173809.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

BLOC1S2 (HGNC:20984): (biogenesis of lysosomal organelles complex 1 subunit 2) This gene encodes a protein with multiple functions. The encoded protein has been found in association with the centrosome, shown to co-localize with gamma-tubulin, and also found to be one of the proteins in the BLOC-1 complex which functions in the formation of lysosome-related organelles. A pseudogene of this gene is located on the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S2	NM_173809.5	c.371A>T	p.Lys124Met	missense_variant	Exon 4 of 5	ENST00000370372.7	NP_776170.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S2	ENST00000370372.7	c.371A>T	p.Lys124Met	missense_variant	Exon 4 of 5	1	NM_173809.5	ENSP00000359398.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461540 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371A>T (p.K124M) alteration is located in exon 4 (coding exon 4) of the BLOC1S2 gene. This alteration results from a A to T substitution at nucleotide position 371, causing the lysine (K) at amino acid position 124 to be replaced by a methionine (M). 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	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	.;.;.;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	.;.;D;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.012	.;.;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.62
MutPred		0.57		.;.;.;Loss of ubiquitination at K124 (P = 0.0155);.;
MVP		0.44
MPC		1.6
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.35
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-102039907;