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: Labcorp Genetics (formerly Invitae), ClinGen, 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=-0.92).
• 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.

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.*982T>C		3_prime_UTR	Exon 20 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.*982T>C		3_prime_UTR	Exon 20 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.*982T>C		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.*982T>C		3_prime_UTR	Exon 20 of 20	ENSP00000355310.4	Q92902-1
	ENSG00000289758	ENST00000699159.1		n.*1486+478T>C		intron	N/A	ENSP00000514167.1	A0A8V8TP71
	HPS1	ENST00000699134.1		c.*982T>C		3_prime_UTR	Exon 19 of 19	ENSP00000514151.1	A0A8V8TPJ1

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

ClinVar submissions as Germline

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	-0.92
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;