10-98431163-G-A

Variant names:

• chr10-98431163-G-A
• rs1801287
• NM_000195.5:c.636C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001311345.2(HPS1):​c.-238C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,542 control chromosomes in the GnomAD database, including 75,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6026 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69024 hom.)
• Consequence: HPS1 NM_001311345.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.69
• Publications: 15 publications found

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]

ENSG00000289758 (HGNC:):

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.086).
• BP6: Variant 10-98431163-G-A is Benign according to our data. Variant chr10-98431163-G-A is described in ClinVar as Benign. ClinVar VariationId is 167185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001311345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	NM_000195.5	MANE Select	c.636C>T	p.Leu212Leu	synonymous	Exon 7 of 20	NP_000186.2
	HPS1	NM_001311345.2		c.-238C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 19	NP_001298274.1
	HPS1	NM_001322487.2		c.-337C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 20	NP_001309416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.636C>T	p.Leu212Leu	synonymous	Exon 7 of 20	ENSP00000355310.4	Q92902-1
	HPS1	ENST00000338546.9	TSL:1	c.636C>T	p.Leu212Leu	synonymous	Exon 7 of 10	ENSP00000343638.5	Q92902-3
	HPS1	ENST00000467246.5	TSL:1	n.*94C>T		non_coding_transcript_exon	Exon 7 of 19	ENSP00000514163.1	A0A8V8TP71

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40425 AN: 152020 Hom.: 6028 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.316 AC: 78552 AN: 248344 AF XY: 0.325

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.303 AC: 442519 AN: 1461404 Hom.: 69024 Cov.: 38 AF XY: 0.308 AC XY: 223610 AN XY: 727002

African (AFR) AF: 0.136 AC: 4546 AN: 33478

American (AMR) AF: 0.334 AC: 14896 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7491 AN: 26132

East Asian (EAS) AF: 0.340 AC: 13498 AN: 39662

South Asian (SAS) AF: 0.427 AC: 36785 AN: 86224

European-Finnish (FIN) AF: 0.347 AC: 18529 AN: 53356

Middle Eastern (MID) AF: 0.328 AC: 1890 AN: 5768

European-Non Finnish (NFE) AF: 0.294 AC: 326897 AN: 1111736

Other (OTH) AF: 0.298 AC: 17987 AN: 60384

GnomAD4 genome AF: 0.266 AC: 40434 AN: 152138 Hom.: 6026 Cov.: 33 AF XY: 0.273 AC XY: 20272 AN XY: 74362

African (AFR) AF: 0.141 AC: 5859 AN: 41536

American (AMR) AF: 0.320 AC: 4888 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3468

East Asian (EAS) AF: 0.345 AC: 1778 AN: 5156

South Asian (SAS) AF: 0.403 AC: 1941 AN: 4822

European-Finnish (FIN) AF: 0.366 AC: 3863 AN: 10566

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20231 AN: 67988

Other (OTH) AF: 0.263 AC: 555 AN: 2114

Alfa AF: 0.282 Hom.: 19190

Bravo AF: 0.253

Asia WGS AF: 0.340 AC: 1180 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.298

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hermansky-Pudlak syndrome 1 (2)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.25
DANN	Benign	0.87
PhyloP100		-1.7
PromoterAI		0.033	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs1801287; hg19: chr10-100190920; COSMIC: COSV57266367; COSMIC: COSV57266367;