6-8041263-T-G

Variant names:

• chr6-8041263-T-G
• rs780995130
• NM_201280.3:c.201A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_201280.3(BLOC1S5):​c.201A>C​(p.Lys67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BLOC1S5 NM_201280.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201280.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S5	NM_201280.3	MANE Select	c.201A>C	p.Lys67Asn	missense	Exon 3 of 5	NP_958437.1	Q8TDH9-1
	BLOC1S5	NM_001199322.1		c.9A>C	p.Lys3Asn	missense	Exon 4 of 6	NP_001186251.1	Q8TDH9-3
	BLOC1S5	NM_001199323.1		c.196-14838A>C		intron	N/A	NP_001186252.1	A0A0A0MTN6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S5	ENST00000397457.7	TSL:1 MANE Select	c.201A>C	p.Lys67Asn	missense	Exon 3 of 5	ENSP00000380598.2	Q8TDH9-1
	BLOC1S5	ENST00000244777.6	TSL:1	n.201A>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000244777.2	G5E931
	EEF1E1-BLOC1S5	ENST00000397456.2	TSL:3	n.*17A>C		non_coding_transcript_exon	Exon 5 of 7	ENSP00000380597.2	C9J1V9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245692 AF XY: 0.00000754

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456070 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724172

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.00 AC: 0 AN: 43812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 84830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110174

Other (OTH) AF: 0.00 AC: 0 AN: 60204

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	0.056
Eigen_PC	Benign	0.0014
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.68
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.57		Loss of methylation at K67 (P = 0.0037)
MVP		0.57
MPC		0.44
ClinPred		0.97	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.58
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs780995130; hg19: chr6-8041496;