rs2296435

Variant names:

• chr10-98422528-T-C
• rs2296435
• NM_000195.5:c.1599-15A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000195.5(HPS1):​c.1599-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,612,042 control chromosomes in the GnomAD database, including 52,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.22 (4245 hom., cov: 33)
  • Exomes 𝑓: 0.25 (47860 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.670
• 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 -18 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-98422528-T-C is Benign according to our data. Variant chr10-98422528-T-C is described in ClinVar as Benign. ClinVar VariationId is 167184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.379 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.1599-15A>G		intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.1599-15A>G		intron	N/A	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1599-15A>G		intron	N/A	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.1599-15A>G		intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*958-15A>G		intron	N/A	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*958-15A>G		intron	N/A	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33978 AN: 152018 Hom.: 4242 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.271 AC: 67930 AN: 250900 AF XY: 0.277

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.249 AC: 363790 AN: 1459906 Hom.: 47860 Cov.: 36 AF XY: 0.254 AC XY: 184776 AN XY: 726354

African (AFR) AF: 0.135 AC: 4513 AN: 33462

American (AMR) AF: 0.303 AC: 13547 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 8155 AN: 26120

East Asian (EAS) AF: 0.362 AC: 14344 AN: 39678

South Asian (SAS) AF: 0.405 AC: 34936 AN: 86206

European-Finnish (FIN) AF: 0.231 AC: 12256 AN: 52972

Middle Eastern (MID) AF: 0.305 AC: 1759 AN: 5766

European-Non Finnish (NFE) AF: 0.233 AC: 258923 AN: 1110664

Other (OTH) AF: 0.255 AC: 15357 AN: 60322

GnomAD4 genome AF: 0.223 AC: 33993 AN: 152136 Hom.: 4245 Cov.: 33 AF XY: 0.228 AC XY: 16935 AN XY: 74370

African (AFR) AF: 0.135 AC: 5620 AN: 41528

American (AMR) AF: 0.283 AC: 4327 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1080 AN: 3464

East Asian (EAS) AF: 0.356 AC: 1832 AN: 5140

South Asian (SAS) AF: 0.394 AC: 1895 AN: 4814

European-Finnish (FIN) AF: 0.223 AC: 2364 AN: 10588

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16105 AN: 67982

Other (OTH) AF: 0.218 AC: 461 AN: 2116

Alfa AF: 0.237 Hom.: 1106

Bravo AF: 0.219

Asia WGS AF: 0.330 AC: 1146 AN: 3478

ClinVar

ClinVar submissions

Significance: 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		0.67
BranchPoint Hunter		3.0
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: rs2296435; hg19: chr10-100182285; COSMIC: COSV57267541; COSMIC: COSV57267541;