10-102065518-C-T

Position:

• chr10-102065518-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024747.6(HPS6):​c.44C>T​(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,402,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPS6 NM_024747.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057699144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS6	NM_024747.6	c.44C>T	p.Ala15Val	missense_variant	1/1	ENST00000299238.7	NP_079023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS6	ENST00000299238.7	c.44C>T	p.Ala15Val	missense_variant	1/1		NM_024747.6	ENSP00000299238	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1402484 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 695822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The c.44C>T (p.A15V) 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 44, causing the alanine (A) at amino acid position 15 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	0.14	T
Polyphen		0.013	B
Vest4		0.061
MutPred		0.16		Loss of disorder (P = 0.0572);
MVP		0.10
MPC		0.49
ClinPred		0.26	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.073
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: rs764430976; hg19: chr10-103825275;