NM_000195.5:c.297C>T

Variant names:

• chr10-98435373-G-A
• rs11539873
• NM_000195.5:c.297C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000195.5(HPS1):​c.297C>T​(p.Thr99Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,862 control chromosomes in the GnomAD database, including 3,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (250 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2939 hom.)
• Consequence: HPS1 NM_000195.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.47
• Publications: 16 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-98435373-G-A is Benign according to our data. Variant chr10-98435373-G-A is described in ClinVar as Benign. ClinVar VariationId is 163666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.297C>T	p.Thr99Thr	synonymous_variant	Exon 5 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.297C>T	p.Thr99Thr	synonymous_variant	Exon 5 of 20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.297C>T		non_coding_transcript_exon_variant	Exon 5 of 24			ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7725 AN: 152036 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0541

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.0677

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.0656 AC: 16495 AN: 251304 AF XY: 0.0640

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0662

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0613 AC: 89555 AN: 1461708 Hom.: 2939 Cov.: 32 AF XY: 0.0606 AC XY: 44093 AN XY: 727160

African (AFR) AF: 0.0101 AC: 337 AN: 33478

American (AMR) AF: 0.0649 AC: 2903 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3030 AN: 26136

East Asian (EAS) AF: 0.121 AC: 4807 AN: 39698

South Asian (SAS) AF: 0.0336 AC: 2895 AN: 86258

European-Finnish (FIN) AF: 0.0683 AC: 3639 AN: 53268

Middle Eastern (MID) AF: 0.0928 AC: 535 AN: 5768

European-Non Finnish (NFE) AF: 0.0605 AC: 67280 AN: 1111988

Other (OTH) AF: 0.0684 AC: 4129 AN: 60392

GnomAD4 genome AF: 0.0507 AC: 7719 AN: 152154 Hom.: 250 Cov.: 32 AF XY: 0.0526 AC XY: 3914 AN XY: 74368

African (AFR) AF: 0.0124 AC: 515 AN: 41532

American (AMR) AF: 0.0541 AC: 827 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.136 AC: 702 AN: 5144

South Asian (SAS) AF: 0.0362 AC: 174 AN: 4802

European-Finnish (FIN) AF: 0.0677 AC: 717 AN: 10594

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0610 AC: 4147 AN: 67996

Other (OTH) AF: 0.0691 AC: 146 AN: 2114

Alfa AF: 0.0565 Hom.: 200

Bravo AF: 0.0497

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0664

EpiControl AF: 0.0672

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr99Thr in exon 5 of HPS1: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 6.0% (512/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11539873). -

Hermansky-Pudlak syndrome 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.023
DANN	Benign	0.79
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11539873; hg19: chr10-100195130; COSMIC: COSV57266384; COSMIC: COSV57266384;