6-8041175-T-C

Variant names:

• chr6-8041175-T-C
• NM_201280.3:c.289A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201280.3(BLOC1S5):​c.289A>G​(p.Thr97Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLOC1S5 NM_201280.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.303

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]

EEF1E1-BLOC1S5 (HGNC:49187): (EEF1E1-BLOC1S5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) and MUTED (muted homolog) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

BLOC1S5-TXNDC5 (HGNC:42001): (BLOC1S5-TXNDC5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MUTED (muted homolog) and TXNDC5 (thioredoxin domain containing 5) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

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=0.037572354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S5	NM_201280.3	c.289A>G	p.Thr97Ala	missense_variant	Exon 3 of 5	ENST00000397457.7	NP_958437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S5	ENST00000397457.7	c.289A>G	p.Thr97Ala	missense_variant	Exon 3 of 5	1	NM_201280.3	ENSP00000380598.2
EEF1E1-BLOC1S5	ENST00000397456.2	n.*105A>G		non_coding_transcript_exon_variant	Exon 5 of 7	3		ENSP00000380597.2
BLOC1S5-TXNDC5	ENST00000439343.2	n.277A>G		non_coding_transcript_exon_variant	Exon 3 of 13	2		ENSP00000454697.1
EEF1E1-BLOC1S5	ENST00000397456.2	n.*105A>G		3_prime_UTR_variant	Exon 5 of 7	3		ENSP00000380597.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.289A>G (p.T97A) alteration is located in exon 3 (coding exon 3) of the BLOC1S5 gene. This alteration results from a A to G substitution at nucleotide position 289, causing the threonine (T) at amino acid position 97 to be replaced by an alanine (A). 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	0.072
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.93
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.050
Sift	Benign	0.59	T
Sift4G	Benign	0.48	T
Polyphen		0.17	B
Vest4		0.11
MutPred		0.16		Loss of phosphorylation at T97 (P = 0.0896);
MVP		0.15
MPC		0.068
ClinPred		0.093	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.10

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-8041408;