rs753410327

Variant names:

• chr10-102065491-C-T
• rs753410327
• NM_024747.6:c.17C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024747.6(HPS6):​c.17C>T​(p.Thr6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,409,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: HPS6 NM_024747.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.690

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2004452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS6	NM_024747.6	c.17C>T	p.Thr6Ile	missense_variant	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.17C>T	p.Thr6Ile	missense_variant	Exon 1 of 1	6	NM_024747.6	ENSP00000299238.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000416 AC: 7 AN: 168320 Hom.: 0 AF XY: 0.0000105 AC XY: 1 AN XY: 94876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000497 AC: 7 AN: 1409122 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000170

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000183 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17C>T (p.T6I) alteration is located in exon 1 (coding exon 1) of the HPS6 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the threonine (T) at amino acid position 6 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 6 of the HPS6 protein (p.Thr6Ile). This variant is present in population databases (rs753410327, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HPS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1353976). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.077
Sift	Benign	0.030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.37
MutPred		0.22		Loss of phosphorylation at T6 (P = 0.0394);
MVP		0.25
MPC		1.0
ClinPred		0.59	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs753410327; hg19: chr10-103825248;