rs12571249

Variant names:

• chr10-98427202-A-G
• rs12571249
• NM_000195.5:c.987+13T>C

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.987+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,550,062 control chromosomes in the GnomAD database, including 1,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (363 hom., cov: 33)
  • Exomes 𝑓: 0.015 (680 hom.)
• Consequence: HPS1 NM_000195.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.962
• Publications: 4 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=-0.92).
• BP6: Variant 10-98427202-A-G is Benign according to our data. Variant chr10-98427202-A-G is described in ClinVar as Benign. ClinVar VariationId is 255506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 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.987+13T>C		intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.987+13T>C		intron	N/A	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.987+13T>C		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.987+13T>C		intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*346+13T>C		intron	N/A	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*346+13T>C		intron	N/A	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6801 AN: 152218 Hom.: 362 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0856

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00708

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0283 AC: 4416 AN: 156290 AF XY: 0.0296

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00987

Gnomad ASJ exome AF: 0.00720

Gnomad EAS exome AF: 0.0801

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0150 AC: 20999 AN: 1397726 Hom.: 680 Cov.: 30 AF XY: 0.0162 AC XY: 11188 AN XY: 689522

African (AFR) AF: 0.128 AC: 4054 AN: 31550

American (AMR) AF: 0.0124 AC: 441 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 178 AN: 25152

East Asian (EAS) AF: 0.0562 AC: 2016 AN: 35842

South Asian (SAS) AF: 0.0680 AC: 5382 AN: 79162

European-Finnish (FIN) AF: 0.000937 AC: 46 AN: 49084

Middle Eastern (MID) AF: 0.0162 AC: 92 AN: 5688

European-Non Finnish (NFE) AF: 0.00677 AC: 7299 AN: 1077592

Other (OTH) AF: 0.0257 AC: 1491 AN: 57962

GnomAD4 genome AF: 0.0448 AC: 6822 AN: 152336 Hom.: 363 Cov.: 33 AF XY: 0.0443 AC XY: 3300 AN XY: 74492

African (AFR) AF: 0.122 AC: 5079 AN: 41570

American (AMR) AF: 0.0225 AC: 345 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.0745 AC: 386 AN: 5178

South Asian (SAS) AF: 0.0854 AC: 413 AN: 4834

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10630

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00709 AC: 482 AN: 68028

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0214 Hom.: 28

Bravo AF: 0.0487

Asia WGS AF: 0.0930 AC: 322 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.015
DANN	Benign	0.22
PhyloP100		-0.96
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: rs12571249; hg19: chr10-100186959;