rs2296430

Variant names:

• chr10-98435826-T-A
• rs2296430
• NM_000195.5:c.118-54A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-98435826-T-A
• chr10-98435826-T-G

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.118-54A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,610,376 control chromosomes in the GnomAD database, including 75,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9089 hom., cov: 31)
  • Exomes 𝑓: 0.30 (66518 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.210
• Publications: 7 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=-0.95).
• BP6: Variant 10-98435826-T-A is Benign according to our data. Variant chr10-98435826-T-A is described in ClinVar as Benign. ClinVar VariationId is 1180583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 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.118-54A>T		intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.118-54A>T		intron	N/A	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.118-54A>T		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.118-54A>T		intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000338546.9	TSL:1	c.118-54A>T		intron	N/A	ENSP00000343638.5	Q92902-3
	HPS1	ENST00000467246.5	TSL:1	n.118-54A>T		intron	N/A	ENSP00000514163.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50500 AN: 151618 Hom.: 9078 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.306

GnomAD4 exome AF: 0.298 AC: 434081 AN: 1458642 Hom.: 66518 AF XY: 0.299 AC XY: 217336 AN XY: 725788

African (AFR) AF: 0.472 AC: 15785 AN: 33416

American (AMR) AF: 0.175 AC: 7821 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6547 AN: 26070

East Asian (EAS) AF: 0.279 AC: 11052 AN: 39644

South Asian (SAS) AF: 0.345 AC: 29710 AN: 86132

European-Finnish (FIN) AF: 0.267 AC: 14245 AN: 53254

Middle Eastern (MID) AF: 0.278 AC: 1594 AN: 5732

European-Non Finnish (NFE) AF: 0.296 AC: 328843 AN: 1109454

Other (OTH) AF: 0.307 AC: 18484 AN: 60266

GnomAD4 genome AF: 0.333 AC: 50546 AN: 151734 Hom.: 9089 Cov.: 31 AF XY: 0.329 AC XY: 24385 AN XY: 74116

African (AFR) AF: 0.465 AC: 19222 AN: 41362

American (AMR) AF: 0.234 AC: 3572 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.284 AC: 1458 AN: 5134

South Asian (SAS) AF: 0.372 AC: 1784 AN: 4790

European-Finnish (FIN) AF: 0.256 AC: 2696 AN: 10520

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 19994 AN: 67882

Other (OTH) AF: 0.307 AC: 649 AN: 2112

Alfa AF: 0.308 Hom.: 966

Bravo AF: 0.333

Asia WGS AF: 0.334 AC: 1159 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.5
DANN	Benign	0.49
PhyloP100		0.21
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: rs2296430; hg19: chr10-100195583; COSMIC: COSV57269577; COSMIC: COSV57269577;