rs746169154

Variant names:

• chr10-98422520-G-T
• rs746169154
• NM_000195.5:c.1599-7C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000195.5(HPS1):​c.1599-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HPS1 NM_000195.5 splice_region, intron
• Scores: Splicing: ADA: 0.002284
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.80
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-98422520-G-T is Benign according to our data. Variant chr10-98422520-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 255502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1599-7C>A		splice_region intron	N/A	NP_000186.2
	HPS1	NM_001322476.2		c.1599-7C>A		splice_region intron	N/A	NP_001309405.1	Q92902-1
	HPS1	NM_001322477.2		c.1599-7C>A		splice_region 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.1599-7C>A		splice_region intron	N/A	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000467246.5	TSL:1	n.*958-7C>A		splice_region intron	N/A	ENSP00000514163.1	A0A8V8TP71
	ENSG00000289758	ENST00000699159.1		n.*958-7C>A		splice_region intron	N/A	ENSP00000514167.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251158 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461522 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727074

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74366

African (AFR) AF: 0.000338 AC: 14 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
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: rs746169154; hg19: chr10-100182277;