rs1801286

chr10-98431242-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000195.5(HPS1):c.557C>T(p.Ala186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,613,940 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A186A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (70 hom.)
• Consequence: HPS1 NM_000195.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.77

Genes affected

HPS1 (HGNC:5163): (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22. [provided by RefSeq, Aug 2015]

MIR4685 (HGNC:41802): (microRNA 4685) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071870685).
• BP6: Variant 10-98431242-G-A is Benign according to our data. Variant chr10-98431242-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-98431242-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00198 (301/152328) while in subpopulation SAS AF= 0.0226 (109/4830). AF 95% confidence interval is 0.0191. There are 4 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS1	NM_000195.5	c.557C>T	p.Ala186Val	missense_variant	7/20	ENST00000361490.9
MIR4685	NR_039833.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS1	ENST00000361490.9	c.557C>T	p.Ala186Val	missense_variant	7/20	1	NM_000195.5	P1
MIR4685	ENST00000578185.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152210 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00458 AC: 1142 AN: 249566 Hom.: 28 AF XY: 0.00624 AC XY: 843 AN XY: 135180

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00273 AC: 3995 AN: 1461612 Hom.: 70 Cov.: 33 AF XY: 0.00366 AC XY: 2662 AN XY: 727114

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152328 Hom.: 4 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74484

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00487 AC: 591

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 13, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hermansky-Pudlak syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Hermansky-Pudlak syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.90
DEOGEN2	Benign	0.070	T;T;T;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.69	D
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.91	N;N;.;N;N
REVEL	Benign	0.054
Sift	Benign	1.0	T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.021	B;B;B;.;B
Vest4		0.13
MVP		0.27
MPC		0.15
ClinPred		0.0038	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.15

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: rs1801286; hg19: chr10-100190999; COSMIC: COSV57269757; COSMIC: COSV57269757;