rs539822608

Variant names:

• chr10-98430661-G-A
• rs539822608
• NM_000195.5:c.678C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000195.5(HPS1):​c.678C>T​(p.Ala226Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,552,812 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HPS1 NM_000195.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.401
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 10-98430661-G-A is Benign according to our data. Variant chr10-98430661-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00144 (220/152266) while in subpopulation AFR AF = 0.00498 (207/41556). AF 95% confidence interval is 0.00443. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	NM_000195.5	MANE Select	c.678C>T	p.Ala226Ala	synonymous	Exon 8 of 20	NP_000186.2
	HPS1	NM_001322490.2		c.560C>T	p.Pro187Leu	missense	Exon 7 of 9	NP_001309419.1
	HPS1	NM_001322492.2		c.560C>T	p.Pro187Leu	missense	Exon 7 of 8	NP_001309421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.678C>T	p.Ala226Ala	synonymous	Exon 8 of 20	ENSP00000355310.4
	HPS1	ENST00000338546.9	TSL:1	c.678C>T	p.Ala226Ala	synonymous	Exon 8 of 10	ENSP00000343638.5
	HPS1	ENST00000467246.5	TSL:1	n.*136C>T		non_coding_transcript_exon	Exon 8 of 19	ENSP00000514163.1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000394 AC: 62 AN: 157428 AF XY: 0.000253

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000492

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000136 AC: 191 AN: 1400546 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 86 AN XY: 690932

African (AFR) AF: 0.00503 AC: 160 AN: 31778

American (AMR) AF: 0.000139 AC: 5 AN: 35896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36160

South Asian (SAS) AF: 0.00 AC: 0 AN: 79324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48890

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5496

European-Non Finnish (NFE) AF: 0.00000741 AC: 8 AN: 1079758

Other (OTH) AF: 0.000276 AC: 16 AN: 58052

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74452

African (AFR) AF: 0.00498 AC: 207 AN: 41556

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.78
DANN	Benign	0.88
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs539822608; hg19: chr10-100190418;