ENST00000338546.9:c.*154T>C

Variant names:

• chr10-98429381-A-G
• rs1061135
• ENST00000338546.9:c.*154T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000338546.9(HPS1):​c.*154T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,525,900 control chromosomes in the GnomAD database, including 229,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22256 hom., cov: 33)
  • Exomes 𝑓: 0.55 (207087 hom.)
• Consequence: HPS1 ENST00000338546.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0810
• Publications: 21 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.86).
• BP6: Variant 10-98429381-A-G is Benign according to our data. Variant chr10-98429381-A-G is described in ClinVar as Benign. ClinVar VariationId is 1180570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000338546.9. 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.937+192T>C		intron	N/A	NP_000186.2
	HPS1	NM_182639.4		c.*154T>C		3_prime_UTR	Exon 10 of 10	NP_872577.1	Q92902-3
	HPS1	NM_001322490.2		c.*84T>C		3_prime_UTR	Exon 9 of 9	NP_001309419.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000338546.9	TSL:1	c.*154T>C		3_prime_UTR	Exon 10 of 10	ENSP00000343638.5	Q92902-3
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.937+192T>C		intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*296+192T>C		intron	N/A	ENSP00000514163.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82038 AN: 151912 Hom.: 22240 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.548 AC: 752256 AN: 1373870 Hom.: 207087 Cov.: 37 AF XY: 0.550 AC XY: 372478 AN XY: 676650

African (AFR) AF: 0.488 AC: 15291 AN: 31346

American (AMR) AF: 0.550 AC: 19445 AN: 35382

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 14311 AN: 24612

East Asian (EAS) AF: 0.610 AC: 21602 AN: 35434

South Asian (SAS) AF: 0.622 AC: 48212 AN: 77524

European-Finnish (FIN) AF: 0.608 AC: 21727 AN: 35716

Middle Eastern (MID) AF: 0.580 AC: 3121 AN: 5380

European-Non Finnish (NFE) AF: 0.538 AC: 576639 AN: 1071162

Other (OTH) AF: 0.557 AC: 31908 AN: 57314

GnomAD4 genome AF: 0.540 AC: 82106 AN: 152030 Hom.: 22256 Cov.: 33 AF XY: 0.550 AC XY: 40876 AN XY: 74300

African (AFR) AF: 0.491 AC: 20379 AN: 41472

American (AMR) AF: 0.548 AC: 8374 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2011 AN: 3470

East Asian (EAS) AF: 0.614 AC: 3174 AN: 5168

South Asian (SAS) AF: 0.623 AC: 3000 AN: 4814

European-Finnish (FIN) AF: 0.625 AC: 6605 AN: 10562

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36809 AN: 67960

Other (OTH) AF: 0.530 AC: 1121 AN: 2114

Alfa AF: 0.540 Hom.: 42257

Bravo AF: 0.529

Asia WGS AF: 0.585 AC: 2033 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	-0.86
CADD	Benign	7.1
DANN	Benign	0.75
PhyloP100		0.081
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1061135;

hg19: chr10-100189138;

COSMIC: COSV57269152;

COSMIC: COSV57269152;