10-102065728-C-G

Variant summary

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

The NM_024747.6(HPS6):c.254C>G(p.Pro85Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000532 in 1,502,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P85L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000030 (1 hom.)
• Consequence: HPS6 NM_024747.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.723

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=0.09848747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS6	NM_024747.6	c.254C>G	p.Pro85Arg	missense_variant	1/1	ENST00000299238.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS6	ENST00000299238.7	c.254C>G	p.Pro85Arg	missense_variant	1/1		NM_024747.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000296 AC: 4 AN: 1350870 Hom.: 1 Cov.: 31 AF XY: 0.00000450 AC XY: 3 AN XY: 666376

Gnomad4 AFR exome AF: 0.0000362

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000264

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151980 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Benign	0.70
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	0.73	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.059
Sift	Benign	0.58	T
Sift4G	Benign	0.67	T
Polyphen		0.0050	B
Vest4		0.28
MutPred		0.54		Gain of solvent accessibility (P = 0.0055);
MVP		0.25
MPC		0.59
ClinPred		0.086	T
GERP RS		2.8
Varity_R		0.040
gMVP		0.26

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: rs544314793; hg19: chr10-103825485;