Genetic Variant HPS6:p.Met1? (chr10-102065475-A-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_024747.6(HPS6):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,404,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HPS6
NM_024747.6 initiator_codon

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.89

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 227 codons. Genomic position: 102066153. Lost 0.292 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-102065475-A-T is Pathogenic according to our data. Variant chr10-102065475-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3590152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS6	NM_024747.6 link	c.1A>T	p.Met1?	initiator_codon_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 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 1	6	NM_024747.6	ENSP00000299238.5		Q86YV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000614

AC:

AN:

162808

Hom.:

AF XY:

0.0000109

AC XY:

AN XY:

92020

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1404054

Hom.:

Cov.:

AF XY:

0.0000201

AC XY:

AN XY:

696934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000228

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000914

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 6

Pathogenic:1

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

MetaSVM

Benign

-0.56

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.57

MutPred

1.0

Loss of MoRF binding (P = 0.1133);

MVP

0.26

ClinPred

0.99

GERP RS

4.8

Varity_R

0.95

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over