chr15-45603169-G-A

Variant names:

• chr15-45603169-G-A
• rs574333116
• NM_012388.4:c.294G>A

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>A​(p.Met98Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

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=0.17467716).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	NM_012388.4	MANE Select	c.294G>A	p.Met98Ile	missense	Exon 3 of 5	NP_036520.1
	BLOC1S6	NM_001311255.1		c.309G>A	p.Met103Ile	missense	Exon 3 of 5	NP_001298184.1
	BLOC1S6	NR_132350.1		n.623G>A		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445924 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 85724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098306

Other (OTH) AF: 0.00 AC: 0 AN: 59880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	19
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.10	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	0.10
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.23		Loss of catalytic residue at M98 (P = 0.0623)
MVP		0.15
MPC		0.45
ClinPred		0.76	D
GERP RS		4.2
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

Other links and lift over

dbSNP: rs574333116; hg19: chr15-45895367;