rs11592273

Variant names:

• chr10-98429811-C-A
• rs11592273
• NM_000195.5:c.847G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-98429811-C-A
• chr10-98429811-C-G
• chr10-98429811-C-T

Variant summary

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

The NM_001322487.2(HPS1):​c.-126G>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 0.0662 in 1,613,760 control chromosomes in the GnomAD database, including 4,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (238 hom., cov: 33)
  • Exomes 𝑓: 0.068 (3776 hom.)
• Consequence: HPS1 NM_001322487.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.55
• Publications: 19 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 (MetaRNN=0.0026259422).
• BP6: Variant 10-98429811-C-A is Benign according to our data. Variant chr10-98429811-C-A is described in ClinVar as Benign. ClinVar VariationId is 21108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322487.2. 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.847G>T	p.Gly283Trp	missense	Exon 9 of 20	NP_000186.2
	HPS1	NM_001322487.2		c.-126G>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 20	NP_001309416.1
	HPS1	NM_001322476.2		c.847G>T	p.Gly283Trp	missense	Exon 9 of 20	NP_001309405.1	Q92902-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.847G>T	p.Gly283Trp	missense	Exon 9 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000338546.9	TSL:1	c.847G>T	p.Gly283Trp	missense	Exon 9 of 10	ENSP00000343638.5	Q92902-3
	HPS1	ENST00000467246.5	TSL:1	n.*227-169G>T		intron	N/A	ENSP00000514163.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.0502 AC: 7645 AN: 152196 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0758

Gnomad OTH AF: 0.0492

GnomAD2 exomes AF: 0.0487 AC: 12218 AN: 251054 AF XY: 0.0489

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.0758

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0679 AC: 99201 AN: 1461446 Hom.: 3776 Cov.: 34 AF XY: 0.0663 AC XY: 48199 AN XY: 727046

African (AFR) AF: 0.0190 AC: 635 AN: 33480

American (AMR) AF: 0.0274 AC: 1225 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 558 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0141 AC: 1220 AN: 86256

European-Finnish (FIN) AF: 0.0684 AC: 3627 AN: 53032

Middle Eastern (MID) AF: 0.0442 AC: 255 AN: 5766

European-Non Finnish (NFE) AF: 0.0793 AC: 88151 AN: 1111960

Other (OTH) AF: 0.0584 AC: 3525 AN: 60392

GnomAD4 genome AF: 0.0502 AC: 7645 AN: 152314 Hom.: 238 Cov.: 33 AF XY: 0.0488 AC XY: 3635 AN XY: 74466

African (AFR) AF: 0.0220 AC: 915 AN: 41588

American (AMR) AF: 0.0361 AC: 552 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4834

European-Finnish (FIN) AF: 0.0641 AC: 681 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0758 AC: 5157 AN: 68012

Other (OTH) AF: 0.0487 AC: 103 AN: 2114

Alfa AF: 0.0615 Hom.: 659

Bravo AF: 0.0472

TwinsUK AF: 0.0809 AC: 300

ALSPAC AF: 0.0693 AC: 267

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.0758 AC: 652

ExAC AF: 0.0511 AC: 6205

EpiCase AF: 0.0696

EpiControl AF: 0.0740

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.29
DANN	Benign	0.78
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.12
Sift	Benign	0.034	D
Sift4G	Benign	0.079	T
Polyphen		0.99	D
Vest4		0.14
MPC		0.49
ClinPred		0.038	T
GERP RS		-5.5
Varity_R		0.029
gMVP		0.22
Mutation Taster		=99/1	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: rs11592273; hg19: chr10-100189568; COSMIC: COSV57266763; COSMIC: COSV57266763;