chr15-45587446-G-C

Variant names:

• chr15-45587446-G-C
• rs1242644356
• NM_012388.4:c.3G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_012388.4(BLOC1S6):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000702 in 1,425,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BLOC1S6 NM_012388.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

Genes affected

BLOC1S6 (HGNC:8549): (biogenesis of lysosomal organelles complex 1 subunit 6) The protein encoded by this gene may play a role in intracellular vesicle trafficking. It interacts with Syntaxin 13 which mediates intracellular membrane fusion. Mutations in this gene cause symptoms associated with Hermansky-Pudlak syndrome-9. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the X chromosome. [provided by RefSeq, Aug 2015]

BLOC1S6 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000260170 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 15 pathogenic variants. Next in-frame start position is after 98 codons. Genomic position: 45603167. Lost 0.563 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	NM_012388.4	MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 5	NP_036520.1	Q9UL45-1
	BLOC1S6	NR_132351.2		n.68G>C		non_coding_transcript_exon	Exon 1 of 5
	BLOC1S6	NR_132352.2		n.68G>C		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	ENST00000220531.9	TSL:1 MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000220531.4	Q9UL45-1
	ENSG00000260170	ENST00000564080.1	TSL:3	c.-97G>C		5_prime_UTR	Exon 1 of 6	ENSP00000455047.1	H3BNX3
	BLOC1S6	ENST00000565216.5	TSL:3	c.3G>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000456067.1	H3BR42

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425254 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 705704

African (AFR) AF: 0.00 AC: 0 AN: 32534

American (AMR) AF: 0.00 AC: 0 AN: 39928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 37584

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092852

Other (OTH) AF: 0.00 AC: 0 AN: 58910

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.79	T
PhyloP100		3.8
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.030	B
Vest4		0.90
MutPred		0.86		Gain of glycosylation at S2 (P = 0.1073)
MVP		0.22
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95

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

Other links and lift over

dbSNP: rs1242644356; hg19: chr15-45879644;