Genetic Variant BLOC1S6:p.Pro27Thr (chr15-45587522-C-A) – 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.79C>A(p.Pro27Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,410 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. P27S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

BLOC1S6
NM_012388.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71

Publications

1 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

BLOC1S6 links:

ENSG00000260170 (HGNC:):

ENSG00000260170 links:

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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=0.060872197).

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
BLOC1S6	NM_012388.4	MANE Select	c.79C>A	p.Pro27Thr	missense	Exon 1 of 5	NP_036520.1
BLOC1S6	NR_132351.2		n.144C>A		non_coding_transcript_exon	Exon 1 of 5
BLOC1S6	NR_132352.2		n.144C>A		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLOC1S6	ENST00000220531.9	TSL:1 MANE Select	c.79C>A	p.Pro27Thr	missense	Exon 1 of 5	ENSP00000220531.4
ENSG00000260170	ENST00000564080.1	TSL:3	c.-21C>A		5_prime_UTR	Exon 1 of 6	ENSP00000455047.1
BLOC1S6	ENST00000565216.5	TSL:3	c.79C>A	p.Pro27Thr	missense	Exon 1 of 5	ENSP00000456067.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

181366

AF XY:

0.00

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:

7.04e-7

AC:

AN:

1420410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32474

American (AMR)

AF:

0.00

AC:

AN:

39398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

37382

South Asian (SAS)

AF:

0.00

AC:

AN:

81448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091804

Other (OTH)

AF:

0.00

AC:

AN:

58754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.22

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.57

M_CAP

Benign

0.0082

MetaRNN

Benign

0.061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

1.7

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.40

REVEL

Benign

0.033

Sift

Benign

0.26

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.20

MutPred

0.28

Gain of phosphorylation at P27 (P = 0.0286)

MVP

0.10

MPC

0.45

ClinPred

0.20

GERP RS

3.7

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.047

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over