NM_000195.5:c.971_972dupCC

Variant names:

• chr10-98427229-T-TGG
• NM_000195.5:c.971_972dupCC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000195.5(HPS1):​c.971_972dupCC​(p.Met325ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,462 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HPS1 NM_000195.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721

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]

ENSG00000289758 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS1	NM_000195.5	c.971_972dupCC	p.Met325ProfsTer7	frameshift_variant	Exon 11 of 20	ENST00000361490.9	NP_000186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS1	ENST00000361490.9	c.971_972dupCC	p.Met325ProfsTer7	frameshift_variant	Exon 11 of 20	1	NM_000195.5	ENSP00000355310.4
ENSG00000289758	ENST00000699159.1	n.*330_*331dupCC		non_coding_transcript_exon_variant	Exon 10 of 24			ENSP00000514167.1
ENSG00000289758	ENST00000699159.1	n.*330_*331dupCC		3_prime_UTR_variant	Exon 10 of 24			ENSP00000514167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385462 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 683686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.36e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-100186986;