rs199816481

Variant names:

• chr10-102065872-C-T
• rs199816481
• NM_024747.6:c.398C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024747.6(HPS6):​c.398C>T​(p.Ala133Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,528,316 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (15 hom.)
• Consequence: HPS6 NM_024747.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.48
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039404333).
• BP6: Variant 10-102065872-C-T is Benign according to our data. Variant chr10-102065872-C-T is described in ClinVar as Benign. ClinVar VariationId is 298554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00294 (448/152254) while in subpopulation NFE AF = 0.00303 (206/68002). AF 95% confidence interval is 0.00269. There are 1 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024747.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS6	NM_024747.6	MANE Select	c.398C>T	p.Ala133Val	missense	Exon 1 of 1	NP_079023.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS6	ENST00000299238.7	TSL:6 MANE Select	c.398C>T	p.Ala133Val	missense	Exon 1 of 1	ENSP00000299238.5

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152140 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00236 AC: 297 AN: 126038 AF XY: 0.00243

Gnomad AFR exome AF: 0.000478

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00292 AC: 4015 AN: 1376062 Hom.: 15 Cov.: 31 AF XY: 0.00293 AC XY: 1987 AN XY: 678408

African (AFR) AF: 0.000382 AC: 12 AN: 31440

American (AMR) AF: 0.000544 AC: 19 AN: 34908

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24762

East Asian (EAS) AF: 0.00 AC: 0 AN: 35764

South Asian (SAS) AF: 0.00186 AC: 147 AN: 78826

European-Finnish (FIN) AF: 0.0186 AC: 620 AN: 33396

Middle Eastern (MID) AF: 0.00140 AC: 6 AN: 4288

European-Non Finnish (NFE) AF: 0.00288 AC: 3097 AN: 1075296

Other (OTH) AF: 0.00197 AC: 113 AN: 57382

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.00347 AC XY: 258 AN XY: 74446

African (AFR) AF: 0.000722 AC: 30 AN: 41560

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10610

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00266 Hom.: 0

Bravo AF: 0.00161

ExAC AF: 0.00152 AC: 137

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hermansky-Pudlak syndrome 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.085
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.029	D
Polyphen		0.22	B
Vest4		0.19
MVP		0.27
MPC		0.49
ClinPred		0.047	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.41
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs199816481; hg19: chr10-103825629;