NM_000195.5:c.636C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000195.5(HPS1):c.636C>T(p.Leu212Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,542 control chromosomes in the GnomAD database, including 75,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6026 hom., cov: 33)

Exomes 𝑓: 0.30 ( 69024 hom. )

Consequence

HPS1
NM_000195.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.69

Variant links:

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 links:

ENSG00000289758 (HGNC:):

ENSG00000289758 links:

MIR4685 (HGNC:41802): (microRNA 4685) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4685 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 10-98431163-G-A is Benign according to our data. Variant chr10-98431163-G-A is described in ClinVar as [Benign]. Clinvar id is 167185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.69 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5 link	c.636C>T	p.Leu212Leu	synonymous_variant	Exon 7 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPS1	ENST00000361490.9 link	c.636C>T	p.Leu212Leu	synonymous_variant	Exon 7 of 20	1	NM_000195.5	ENSP00000355310.4	Q92902-1
ENSG00000289758	ENST00000699159.1 link	n.*94C>T		non_coding_transcript_exon_variant	Exon 7 of 24			ENSP00000514167.1	A0A8V8TP71
ENSG00000289758	ENST00000699159.1 link	n.*94C>T		3_prime_UTR_variant	Exon 7 of 24			ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40425

AN:

152020

Hom.:

6028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.345

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.298

Gnomad OTH

AF:

0.266

GnomAD3 exomes

AF:

0.316

AC:

78552

AN:

248344

Hom.:

13031

AF XY:

0.325

AC XY:

43749

AN XY:

134506

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.333

Gnomad ASJ exome

AF:

0.286

Gnomad EAS exome

AF:

0.332

Gnomad SAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.303

AC:

442519

AN:

1461404

Hom.:

69024

Cov.:

AF XY:

0.308

AC XY:

223610

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.334

Gnomad4 ASJ exome

AF:

0.287

Gnomad4 EAS exome

AF:

0.340

Gnomad4 SAS exome

AF:

0.427

Gnomad4 FIN exome

AF:

0.347

Gnomad4 NFE exome

AF:

0.294

Gnomad4 OTH exome

AF:

0.298

GnomAD4 genome

AF:

0.266

AC:

40434

AN:

152138

Hom.:

6026

Cov.:

AF XY:

0.273

AC XY:

20272

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.320

Gnomad4 ASJ

AF:

0.279

Gnomad4 EAS

AF:

0.345

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.366

Gnomad4 NFE

AF:

0.298

Gnomad4 OTH

AF:

0.263

Alfa

AF:

0.288

Hom.:

8597

Bravo

AF:

0.253

Asia WGS

AF:

0.340

AC:

1180

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu212Leu in exon 7 of HPS1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 29.2% (2515/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1801287). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 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

- -

Hermansky-Pudlak syndrome 1

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

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

-0.71

CADD

Benign

0.25

DANN

Benign

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over