10-98427229-TG-T

Variant names:

• chr10-98427229-TG-T
• rs281865082
• NM_000195.5:c.972delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000195.5(HPS1):​c.972delC​(p.Met325TrpfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,535,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: HPS1 NM_000195.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 0.721
• Publications: 18 publications found

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

HPS1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-98427229-TG-T is Pathogenic according to our data. Variant chr10-98427229-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. 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
	HPS1	NM_000195.5	MANE Select	c.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	NP_001309406.1	Q92902-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.972delC	p.Met325TrpfsTer6	frameshift	Exon 11 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*331delC		non_coding_transcript_exon	Exon 10 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*331delC		non_coding_transcript_exon	Exon 10 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151930 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

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: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000166 AC: 24 AN: 144354 AF XY: 0.000118

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000288

Gnomad FIN exome AF: 0.000857

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000455 AC: 63 AN: 1383570 Hom.: 0 Cov.: 30 AF XY: 0.0000425 AC XY: 29 AN XY: 682764

African (AFR) AF: 0.0000966 AC: 3 AN: 31044

American (AMR) AF: 0.0000566 AC: 2 AN: 35310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24906

East Asian (EAS) AF: 0.0000848 AC: 3 AN: 35386

South Asian (SAS) AF: 0.0000383 AC: 3 AN: 78382

European-Finnish (FIN) AF: 0.000578 AC: 28 AN: 48406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.0000225 AC: 24 AN: 1067228

Other (OTH) AF: 0.00 AC: 0 AN: 57262

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74330

African (AFR) AF: 0.000265 AC: 11 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Hermansky-Pudlak syndrome 1 (8)
2	-	-	Hermansky-Pudlak syndrome (2)
2	-	-	not provided (2)
1	-	-	HPS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs281865082; hg19: chr10-100186986; COSMIC: COSV57267674; COSMIC: COSV57267674;