NM_001487.4:c.4G>A

Variant names:

• chr12-55716055-G-A
• rs933348517
• NM_001487.4:c.4G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001487.4(BLOC1S1):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BLOC1S1 NM_001487.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.472

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]

ENSG00000258311 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07506344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S1	NM_001487.4	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 4	ENST00000548925.6	NP_001478.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S1	ENST00000548925.6	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 4	1	NM_001487.4	ENSP00000447537.1
ENSG00000258311	ENST00000550412.5	c.4G>A	p.Ala2Thr	missense_variant	Exon 1 of 4	2		ENSP00000447650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403856 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 693686

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: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.89
DEOGEN2	Benign	0.055	.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.023
Sift	Uncertain	0.029	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.013	B;.;B
Vest4		0.17
MutPred		0.24		Gain of catalytic residue at P3 (P = 0.005);Gain of catalytic residue at P3 (P = 0.005);Gain of catalytic residue at P3 (P = 0.005);
MVP		0.081
MPC		0.022
ClinPred		0.15	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.051
gMVP		0.077

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

Other links and lift over

dbSNP: rs933348517; hg19: chr12-56109839;