chr10-98424305-C-A

Variant names:

• chr10-98424305-C-A
• rs2296433
• NM_000195.5:c.1397+8G>T

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.1397+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,605,012 control chromosomes in the GnomAD database, including 51,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4112 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46925 hom.)
• Consequence: HPS1 NM_000195.5 splice_region, intron
• Scores: Splicing: ADA: 0.0006200
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.466
• Publications: 12 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=-0.79).
• BP6: Variant 10-98424305-C-A is Benign according to our data. Variant chr10-98424305-C-A is described in ClinVar as Benign. ClinVar VariationId is 163664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.381 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.1397+8G>T		splice_region intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.1397+8G>T		splice_region intron	N/A	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1397+8G>T		splice_region 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.1397+8G>T		splice_region intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*756+8G>T		splice_region intron	N/A	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*756+8G>T		splice_region intron	N/A	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33210 AN: 151912 Hom.: 4108 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.264 AC: 64703 AN: 245248 AF XY: 0.270

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.247 AC: 359167 AN: 1452978 Hom.: 46925 Cov.: 32 AF XY: 0.252 AC XY: 182402 AN XY: 722744

African (AFR) AF: 0.117 AC: 3898 AN: 33354

American (AMR) AF: 0.297 AC: 13116 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8040 AN: 25904

East Asian (EAS) AF: 0.365 AC: 14442 AN: 39564

South Asian (SAS) AF: 0.404 AC: 34461 AN: 85232

European-Finnish (FIN) AF: 0.230 AC: 12207 AN: 53058

Middle Eastern (MID) AF: 0.303 AC: 1743 AN: 5758

European-Non Finnish (NFE) AF: 0.232 AC: 256021 AN: 1105780

Other (OTH) AF: 0.253 AC: 15239 AN: 60132

GnomAD4 genome AF: 0.218 AC: 33219 AN: 152034 Hom.: 4112 Cov.: 33 AF XY: 0.223 AC XY: 16574 AN XY: 74316

African (AFR) AF: 0.118 AC: 4913 AN: 41538

American (AMR) AF: 0.281 AC: 4300 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1077 AN: 3462

East Asian (EAS) AF: 0.369 AC: 1895 AN: 5136

South Asian (SAS) AF: 0.396 AC: 1908 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2357 AN: 10586

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.236 AC: 16013 AN: 67904

Other (OTH) AF: 0.214 AC: 451 AN: 2104

Alfa AF: 0.223 Hom.: 1777

Bravo AF: 0.214

Asia WGS AF: 0.332 AC: 1153 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)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.52
PhyloP100		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.012
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: rs2296433; hg19: chr10-100184062; COSMIC: COSV57267557; COSMIC: COSV57267557;