10-98417552-G-C

Variant names:

• chr10-98417552-G-C
• rs112544050
• ENST00000467246.5:n.*1474C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000467246.5(HPS1):​n.*1474C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPS1 ENST00000467246.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.*12C>G		3_prime_UTR_variant	Exon 20 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.*12C>G		3_prime_UTR_variant	Exon 20 of 20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*1347+127C>G		intron_variant	Intron 19 of 23			ENSP00000514167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722724

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4444

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108500

Other (OTH) AF: 0.00 AC: 0 AN: 59910

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.038
DANN	Benign	0.71
PhyloP100		-2.2

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: rs112544050; hg19: chr10-100177309;