NM_000195.5:c.*982T>C

Variant names:

• chr10-98416582-A-G
• rs1739
• NM_000195.5:c.*982T>C

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.*982T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,282 control chromosomes in the GnomAD database, including 18,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18070 hom., cov: 33)
  • Exomes 𝑓: 0.41 (17 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0520
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-98416582-A-G is Benign according to our data. Variant chr10-98416582-A-G is described in ClinVar as Benign. ClinVar VariationId is 298314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.*982T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.*982T>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*1486+478T>C		intron_variant	Intron 20 of 23			ENSP00000514167.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69988 AN: 151968 Hom.: 18029 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.528

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.413 AC: 81 AN: 196 Hom.: 17 Cov.: 0 AF XY: 0.474 AC XY: 54 AN XY: 114

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.397 AC: 54 AN: 136

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.417 AC: 5 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.417 AC: 15 AN: 36

Other (OTH) AF: 0.583 AC: 7 AN: 12

GnomAD4 genome AF: 0.461 AC: 70082 AN: 152086 Hom.: 18070 Cov.: 33 AF XY: 0.464 AC XY: 34465 AN XY: 74346

African (AFR) AF: 0.687 AC: 28523 AN: 41500

American (AMR) AF: 0.457 AC: 6988 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3468

East Asian (EAS) AF: 0.659 AC: 3395 AN: 5152

South Asian (SAS) AF: 0.527 AC: 2546 AN: 4832

European-Finnish (FIN) AF: 0.311 AC: 3286 AN: 10574

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22424 AN: 67964

Other (OTH) AF: 0.440 AC: 928 AN: 2108

Alfa AF: 0.382 Hom.: 15903

Bravo AF: 0.477

Asia WGS AF: 0.569 AC: 1976 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hermansky-Pudlak syndrome 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.42
PhyloP100		-0.052
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: rs1739; hg19: chr10-100176339; COSMIC: COSV105206670; COSMIC: COSV105206670;