NM_000195.5:c.*452G>A

Variant names:

• chr10-98417112-C-T
• rs701801
• NM_000195.5:c.*452G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000195.5(HPS1):​c.*452G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 156,666 control chromosomes in the GnomAD database, including 13,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12845 hom., cov: 33)
  • Exomes 𝑓: 0.27 (217 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.26
• Publications: 33 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-98417112-C-T is Benign according to our data. Variant chr10-98417112-C-T is described in ClinVar as Benign. ClinVar VariationId is 298329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

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.*452G>A		3_prime_UTR	Exon 20 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.*452G>A		3_prime_UTR	Exon 20 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.*452G>A		3_prime_UTR	Exon 20 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.*452G>A		3_prime_UTR	Exon 20 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*1914G>A		non_coding_transcript_exon	Exon 19 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*1434G>A		non_coding_transcript_exon	Exon 20 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59463 AN: 151772 Hom.: 12802 Cov.: 33

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.269 AC: 1287 AN: 4776 Hom.: 217 Cov.: 0 AF XY: 0.281 AC XY: 665 AN XY: 2368

African (AFR) AF: 0.482 AC: 27 AN: 56

American (AMR) AF: 0.386 AC: 187 AN: 484

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 34 AN: 80

East Asian (EAS) AF: 0.325 AC: 37 AN: 114

South Asian (SAS) AF: 0.372 AC: 93 AN: 250

European-Finnish (FIN) AF: 0.241 AC: 42 AN: 174

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.239 AC: 809 AN: 3382

Other (OTH) AF: 0.246 AC: 57 AN: 232

GnomAD4 genome AF: 0.392 AC: 59559 AN: 151890 Hom.: 12845 Cov.: 33 AF XY: 0.395 AC XY: 29336 AN XY: 74228

African (AFR) AF: 0.570 AC: 23590 AN: 41414

American (AMR) AF: 0.411 AC: 6276 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3468

East Asian (EAS) AF: 0.486 AC: 2492 AN: 5132

South Asian (SAS) AF: 0.396 AC: 1906 AN: 4812

European-Finnish (FIN) AF: 0.276 AC: 2911 AN: 10564

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.291 AC: 19795 AN: 67910

Other (OTH) AF: 0.376 AC: 794 AN: 2114

Alfa AF: 0.327 Hom.: 11041

Bravo AF: 0.406

Asia WGS AF: 0.430 AC: 1494 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.058
DANN	Benign	0.63
PhyloP100		-5.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs701801; hg19: chr10-100176869;