rs11539873

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-98435373-G-A
• chr10-98435373-G-C
• chr10-98435373-G-T

Variant summary

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

The NM_001311345.2(HPS1):​c.-620C>T variant causes a 5 prime UTR premature start codon gain 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_001311345.2 5_prime_UTR_premature_start_codon_gain
• 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: 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 10-98435373-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.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001311345.2. 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.297C>T	p.Thr99Thr	synonymous	Exon 5 of 20	NP_000186.2
	HPS1	NM_001311345.2		c.-620C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 19	NP_001298274.1
	HPS1	NM_001322487.2		c.-719C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 20	NP_001309416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.297C>T	p.Thr99Thr	synonymous	Exon 5 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000338546.9	TSL:1	c.297C>T	p.Thr99Thr	synonymous	Exon 5 of 10	ENSP00000343638.5	Q92902-3
	HPS1	ENST00000467246.5	TSL:1	n.297C>T		non_coding_transcript_exon	Exon 5 of 19	ENSP00000514163.1	A0A8V8TP71

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hermansky-Pudlak syndrome 1 (2)
-	-	2	not specified (2)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;