15-45603169-G-C

Variant names:

• chr15-45603169-G-C
• NM_012388.4:c.294G>C
• BLOC1S6 p.Met98Ile

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012388.4(BLOC1S6):​c.294G>C​(p.Met98Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLOC1S6 NM_012388.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000260170 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19826373).

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.294G>C	p.Met98Ile	missense	Exon 3 of 5	NP_036520.1	Q9UL45-1
	BLOC1S6	NM_001311255.1		c.309G>C	p.Met103Ile	missense	Exon 3 of 5	NP_001298184.1	H3BST1
	BLOC1S6	NM_001311256.1		c.240-2259G>C		intron	N/A	NP_001298185.1	B3KY40

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	ENST00000220531.9	TSL:1 MANE Select	c.294G>C	p.Met98Ile	missense	Exon 3 of 5	ENSP00000220531.4	Q9UL45-1
	ENSG00000260170	ENST00000564080.1	TSL:3	c.-18+15644G>C		intron	N/A	ENSP00000455047.1	H3BNX3
	BLOC1S6	ENST00000562384.5	TSL:4	c.3G>C	p.Met1?	start_lost	Exon 3 of 5	ENSP00000457077.1	H3BRA4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.28
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.14

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-45895367;