10-102065929-C-A

Variant names:

• chr10-102065929-C-A
• rs369112226
• NM_024747.6:c.455C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_024747.6(HPS6):​c.455C>A​(p.Ser152*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,411,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.1e-7 (0 hom.)
• Consequence: HPS6 NM_024747.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.529
• Publications: 0 publications found

Genes affected

HPS6 (HGNC:18817): (HPS6 biogenesis of lysosomal organelles complex 2 subunit 3) This intronless gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 5 protein. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6. [provided by RefSeq, Jul 2008]

HPS6 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 67 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS6	NM_024747.6	c.455C>A	p.Ser152*	stop_gained	Exon 1 of 1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7	c.455C>A	p.Ser152*	stop_gained	Exon 1 of 1	6	NM_024747.6	ENSP00000299238.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411800 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 37992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.00 AC: 0 AN: 37542

South Asian (SAS) AF: 0.00 AC: 0 AN: 82348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096474

Other (OTH) AF: 0.00 AC: 0 AN: 58920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Benign	0.87
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.017	N
PhyloP100		-0.53
Vest4		0.72
GERP RS		-3.3
Mutation Taster		=24/176	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369112226; hg19: chr10-103825686;