rs2296436

Variant names:

• chr10-98420094-T-C
• rs2296436
• NM_000195.5:c.1808A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-98420094-T-C
• chr10-98420094-T-A

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.1808A>G​(p.Gln603Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 1,613,678 control chromosomes in the GnomAD database, including 7,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q603W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (895 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6134 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.34
• Publications: 27 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=0.0013628304).
• BP6: Variant 10-98420094-T-C is Benign according to our data. Variant chr10-98420094-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 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.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1808A>G	p.Gln603Arg	missense	Exon 18 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.1808A>G	p.Gln603Arg	missense	Exon 18 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*1167A>G		non_coding_transcript_exon	Exon 17 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*1167A>G		non_coding_transcript_exon	Exon 17 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16067 AN: 152124 Hom.: 894 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0850

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0999 AC: 25061 AN: 250894 AF XY: 0.0948

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0883

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0884 AC: 129145 AN: 1461436 Hom.: 6134 Cov.: 31 AF XY: 0.0869 AC XY: 63164 AN XY: 727018

African (AFR) AF: 0.140 AC: 4700 AN: 33466

American (AMR) AF: 0.124 AC: 5565 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3066 AN: 26128

East Asian (EAS) AF: 0.121 AC: 4793 AN: 39696

South Asian (SAS) AF: 0.0410 AC: 3539 AN: 86246

European-Finnish (FIN) AF: 0.129 AC: 6883 AN: 53392

Middle Eastern (MID) AF: 0.122 AC: 704 AN: 5768

European-Non Finnish (NFE) AF: 0.0845 AC: 93962 AN: 1111654

Other (OTH) AF: 0.0983 AC: 5933 AN: 60374

GnomAD4 genome AF: 0.106 AC: 16081 AN: 152242 Hom.: 895 Cov.: 33 AF XY: 0.109 AC XY: 8100 AN XY: 74454

African (AFR) AF: 0.132 AC: 5505 AN: 41548

American (AMR) AF: 0.110 AC: 1687 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3468

East Asian (EAS) AF: 0.140 AC: 723 AN: 5180

South Asian (SAS) AF: 0.0424 AC: 204 AN: 4814

European-Finnish (FIN) AF: 0.134 AC: 1417 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0849 AC: 5773 AN: 67998

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.0937 Hom.: 2394

Bravo AF: 0.107

TwinsUK AF: 0.0782 AC: 290

ALSPAC AF: 0.0882 AC: 340

ESP6500AA AF: 0.139 AC: 614

ESP6500EA AF: 0.0847 AC: 728

ExAC AF: 0.0990 AC: 12023

Asia WGS AF: 0.0930 AC: 324 AN: 3478

EpiCase AF: 0.0876

EpiControl AF: 0.0872

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Benign	0.78
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.016
MPC		0.15
ClinPred		0.0032	T
GERP RS		3.4
Varity_R		0.028
gMVP		0.39
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: rs2296436; hg19: chr10-100179851; COSMIC: COSV57268041; COSMIC: COSV57268041;