10-98423754-G-C

Variant names:

• chr10-98423754-G-C
• rs147748659
• NM_000195.5:c.1531C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000195.5(HPS1):​c.1531C>G​(p.Arg511Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPS1 NM_000195.5 missense, splice_region
• Scores: Splicing: ADA: 0.0007237
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21557096).

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.1531C>G	p.Arg511Gly	missense splice_region	Exon 15 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.1531C>G	p.Arg511Gly	missense splice_region	Exon 15 of 20	NP_001309405.1
	HPS1	NM_001322477.2		c.1531C>G	p.Arg511Gly	missense splice_region	Exon 15 of 20	NP_001309406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.1531C>G	p.Arg511Gly	missense splice_region	Exon 15 of 20	ENSP00000355310.4
	HPS1	ENST00000467246.5	TSL:1	n.*890C>G		splice_region non_coding_transcript_exon	Exon 14 of 19	ENSP00000514163.1
	ENSG00000289758	ENST00000699159.1		n.*890C>G		splice_region non_coding_transcript_exon	Exon 14 of 24	ENSP00000514167.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.092
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0090	D
Vest4		0.33
MutPred		0.26		Loss of MoRF binding (P = 0.015)
MVP		0.21
MPC		0.27
ClinPred		0.92	D
GERP RS		2.5
Varity_R		0.13
gMVP		0.26
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00072
dbscSNV1_RF	Benign	0.042
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: rs147748659; hg19: chr10-100183511;