NM_012388.4:c.294G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_012388.4(BLOC1S6):c.294G>T(p.Met98Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000476 in 1,598,094 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

BLOC1S6
NM_012388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.34

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

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13868082).

BP6

Variant 15-45603169-G-T is Benign according to our data. Variant chr15-45603169-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522345.

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.294G>T	p.Met98Ile	missense	Exon 3 of 5	NP_036520.1
BLOC1S6	NM_001311255.1		c.309G>T	p.Met103Ile	missense	Exon 3 of 5	NP_001298184.1
BLOC1S6	NR_132350.1		n.623G>T		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249284

AF XY:

0.0000148

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:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1445922

Hom.:

Cov.:

AF XY:

0.0000514

AC XY:

AN XY:

720292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33138

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.00

AC:

AN:

85724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000546

AC:

AN:

1098304

Other (OTH)

AF:

0.0000334

AC:

AN:

59880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

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:

0.0000920

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

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:

0.0000565

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 9

Uncertain:1Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 98 of the BLOC1S6 protein (p.Met98Ile). This variant is present in population databases (rs574333116, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with BLOC1S6-related conditions. ClinVar contains an entry for this variant (Variation ID: 522345). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.294G>T (p.M98I) alteration is located in exon 3 (coding exon 3) of the BLOC1S6 gene. This alteration results from a G to T substitution at nucleotide position 294, causing the methionine (M) at amino acid position 98 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

not provided

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.0013

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

M_CAP

Benign

0.0021

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

1.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

REVEL

Benign

0.10

Sift

Benign

0.40

Sift4G

Benign

0.60

Polyphen

0.0010

Vest4

0.17

MutPred

0.23

Loss of catalytic residue at M98 (P = 0.0623)

MVP

0.15

MPC

0.45

ClinPred

0.18

GERP RS

4.2

Varity_R

0.073

gMVP

0.14

Mutation Taster

=27/173

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over