10-98431242-G-A

Variant names:

• chr10-98431242-G-A
• rs1801286
• NM_000195.5:c.557C>T

Variant summary

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

The ENST00000361490.9(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. 15/21 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 ENST00000361490.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.77
• Publications: 10 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 -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 Benign/Likely_benign. ClinVar VariationId is 211150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361490.9. 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
	HPS1	NM_000195.5	MANE Select	c.557C>T	p.Ala186Val	missense	Exon 7 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.557C>T	p.Ala186Val	missense	Exon 7 of 20	NP_001309405.1
	HPS1	NM_001322477.2		c.557C>T	p.Ala186Val	missense	Exon 7 of 20	NP_001309406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.557C>T	p.Ala186Val	missense	Exon 7 of 20	ENSP00000355310.4
	HPS1	ENST00000338546.9	TSL:1	c.557C>T	p.Ala186Val	missense	Exon 7 of 10	ENSP00000343638.5
	HPS1	ENST00000467246.5	TSL:1	n.*15C>T		non_coding_transcript_exon	Exon 7 of 19	ENSP00000514163.1

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

GnomAD2 exomes AF: 0.00458 AC: 1142 AN: 249566 AF XY: 0.00624

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 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

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0275 AC: 2368 AN: 86256

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53162

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00111 AC: 1236 AN: 1111996

Other (OTH) AF: 0.00378 AC: 228 AN: 60396

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

African (AFR) AF: 0.000337 AC: 14 AN: 41566

American (AMR) AF: 0.00131 AC: 20 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68032

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00193 Hom.: 3

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.021	B
Vest4		0.13
MVP		0.27
MPC		0.15
ClinPred		0.0038	T
GERP RS		1.4
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.15
Mutation Taster		=100/0	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: rs1801286; hg19: chr10-100190999; COSMIC: COSV57269757; COSMIC: COSV57269757;