Genetic Variant BLOC1S6:p.Arg15Gly (chr15-45587486-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012388.4(BLOC1S6):c.43C>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,585,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. R15W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BLOC1S6
NM_012388.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.925

Publications

0 publications found

Variant links:

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

BLOC1S6 links:

ENSG00000260170 (HGNC:):

ENSG00000260170 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025561005).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLOC1S6	NM_012388.4	MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 1 of 5	NP_036520.1	Q9UL45-1
BLOC1S6	NR_132351.2		n.108C>G		non_coding_transcript_exon	Exon 1 of 5
BLOC1S6	NR_132352.2		n.108C>G		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BLOC1S6	ENST00000220531.9	TSL:1 MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 1 of 5	ENSP00000220531.4	Q9UL45-1
ENSG00000260170	ENST00000564080.1	TSL:3	c.-57C>G		5_prime_UTR	Exon 1 of 6	ENSP00000455047.1	H3BNX3
BLOC1S6	ENST00000565216.5	TSL:3	c.43C>G	p.Arg15Gly	missense	Exon 1 of 5	ENSP00000456067.1	H3BR42

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000495

AC:

AN:

202106

AF XY:

0.00000918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1433590

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

710590

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32786

American (AMR)

AF:

0.00

AC:

AN:

41108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

38110

South Asian (SAS)

AF:

0.0000364

AC:

AN:

82456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097802

Other (OTH)

AF:

0.00

AC:

AN:

59250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000833

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.0

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.13

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0031

LIST_S2

Benign

0.66

M_CAP

Benign

0.0023

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.8

PhyloP100

0.93

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.53

REVEL

Benign

0.089

Sift

Benign

0.96

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.052

MutPred

0.15

Loss of helix (P = 0.079)

MVP

0.095

MPC

0.52

ClinPred

0.040

GERP RS

0.62

PromoterAI

-0.089

Neutral

(source)

Varity_R

0.061

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over