chr10-98416397-C-T

Variant names:

• chr10-98416397-C-T
• rs1061437
• NM_000195.5:c.*1167G>A

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.*1167G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 152,186 control chromosomes in the GnomAD database, including 10,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10582 hom., cov: 33)
  • Exomes 𝑓: 0.32 (10 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.24
• Publications: 27 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: Labcorp Genetics (formerly Invitae), ClinGen, 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=-0.94).
• BP6: Variant 10-98416397-C-T is Benign according to our data. Variant chr10-98416397-C-T is described in ClinVar as Benign. ClinVar VariationId is 298311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 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.*1167G>A		3_prime_UTR	Exon 20 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.*1167G>A		3_prime_UTR	Exon 20 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.*1167G>A		3_prime_UTR	Exon 20 of 20	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.*1167G>A		3_prime_UTR	Exon 20 of 20	ENSP00000355310.4	Q92902-1
	ENSG00000289758	ENST00000699159.1		n.*1487-641G>A		intron	N/A	ENSP00000514167.1	A0A8V8TP71
	HPS1	ENST00000699134.1		c.*1167G>A		3_prime_UTR	Exon 19 of 19	ENSP00000514151.1	A0A8V8TPJ1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53849 AN: 151890 Hom.: 10566 Cov.: 33

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.330

GnomAD4 exome AF: 0.320 AC: 57 AN: 178 Hom.: 10 Cov.: 0 AF XY: 0.357 AC XY: 35 AN XY: 98

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.312 AC: 43 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.300 AC: 3 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.308 AC: 8 AN: 26

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.355 AC: 53914 AN: 152008 Hom.: 10582 Cov.: 33 AF XY: 0.355 AC XY: 26374 AN XY: 74300

African (AFR) AF: 0.515 AC: 21344 AN: 41458

American (AMR) AF: 0.380 AC: 5799 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3470

East Asian (EAS) AF: 0.428 AC: 2208 AN: 5154

South Asian (SAS) AF: 0.483 AC: 2327 AN: 4814

European-Finnish (FIN) AF: 0.211 AC: 2223 AN: 10556

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17766 AN: 67968

Other (OTH) AF: 0.330 AC: 696 AN: 2112

Alfa AF: 0.295 Hom.: 9235

Bravo AF: 0.368

Asia WGS AF: 0.451 AC: 1565 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.36
PhyloP100		-3.2
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: rs1061437; hg19: chr10-100176154; COSMIC: COSV105206669; COSMIC: COSV105206669;