10-98422414-C-T

Variant names:

• chr10-98422414-C-T
• rs148450315
• NM_000195.5:c.1698G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000195.5(HPS1):​c.1698G>A​(p.Ser566Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,614,154 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S566S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (83 hom.)
• Consequence: HPS1 NM_000195.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.67
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-98422414-C-T is Benign according to our data. Variant chr10-98422414-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00573 (873/152294) while in subpopulation NFE AF = 0.00969 (659/68024). AF 95% confidence interval is 0.00908. There are 1 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 83 AR gene

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.1698G>A	p.Ser566Ser	synonymous	Exon 17 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1698G>A	p.Ser566Ser	synonymous	Exon 17 of 20	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1698G>A	p.Ser566Ser	synonymous	Exon 17 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.1698G>A	p.Ser566Ser	synonymous	Exon 17 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*1057G>A		non_coding_transcript_exon	Exon 16 of 19	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*1057G>A		non_coding_transcript_exon	Exon 16 of 24	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 873 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00573 AC: 1440 AN: 251480 AF XY: 0.00569

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00981

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00809 AC: 11824 AN: 1461860 Hom.: 83 Cov.: 37 AF XY: 0.00775 AC XY: 5634 AN XY: 727226

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.00313 AC: 140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00670 AC: 358 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00969 AC: 10770 AN: 1111982

Other (OTH) AF: 0.00765 AC: 462 AN: 60392

GnomAD4 genome AF: 0.00573 AC: 873 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00533 AC XY: 397 AN XY: 74470

African (AFR) AF: 0.00180 AC: 75 AN: 41556

American (AMR) AF: 0.00307 AC: 47 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00678 AC: 72 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 68024

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00722 Hom.: 1

Bravo AF: 0.00515

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00776

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (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	-0.60
CADD	Benign	0.39
DANN	Benign	0.48
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148450315; hg19: chr10-100182171;