chr6-8064352-G-A

Position:

chr6-8064352-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_201280.3(BLOC1S5):c.25C>T(p.Pro9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,611,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P9L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

BLOC1S5
NM_201280.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0320

Variant links:

Genes affected

BLOC1S5 (HGNC:18561): (biogenesis of lysosomal organelles complex 1 subunit 5) This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet-dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene. [provided by RefSeq, Dec 2010]

BLOC1S5 links:

BLOC1S5-TXNDC5 (HGNC:):

BLOC1S5-TXNDC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015609592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BLOC1S5	NM_201280.3 linkuse as main transcript	c.25C>T	p.Pro9Ser	missense_variant	1/5	ENST00000397457.7
BLOC1S5-TXNDC5	NR_037616.1 linkuse as main transcript	n.63C>T		non_coding_transcript_exon_variant	1/13
EEF1E1-BLOC1S5	NR_037618.1 linkuse as main transcript	n.459-1736C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S5	ENST00000397457.7 linkuse as main transcript	c.25C>T	p.Pro9Ser	missense_variant	1/5	1	NM_201280.3	P1	Q8TDH9-1
BLOC1S5	ENST00000244777.6 linkuse as main transcript	c.25C>T	p.Pro9Ser	missense_variant, NMD_transcript_variant	1/6	1
BLOC1S5	ENST00000627748.2 linkuse as main transcript	c.25C>T	p.Pro9Ser	missense_variant, NMD_transcript_variant	1/6	1
BLOC1S5	ENST00000543936.7 linkuse as main transcript	c.25C>T	p.Pro9Ser	missense_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000974

AC:

AN:

246434

Hom.:

AF XY:

0.0000746

AC XY:

AN XY:

134016

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1459560

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

726250

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000256

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.25C>T (p.P9S) alteration is located in exon 1 (coding exon 1) of the BLOC1S5 gene. This alteration results from a C to T substitution at nucleotide position 25, causing the proline (P) at amino acid position 9 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.11

Sift

Benign

0.095

T;.

Sift4G

Uncertain

0.021

D;D

Polyphen

0.0050

B;.

Vest4

0.19

MVP

0.24

MPC

0.083

ClinPred

0.012

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.046

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over