rs112544050

Variant names:

• chr10-98417552-G-A
• rs112544050
• NM_000195.5:c.*12C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-98417552-G-A
• chr10-98417552-G-C

Variant summary

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

The NM_000195.5(HPS1):​c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,606,024 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: HPS1 NM_000195.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.16
• Publications: 0 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]

HPS1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289758 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-98417552-G-A is Benign according to our data. Variant chr10-98417552-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255497.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 = 0.00338 (514/152246) while in subpopulation NFE AF = 0.00506 (344/67986). AF 95% confidence interval is 0.00462. There are 3 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000195.5. 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.*12C>T		3_prime_UTR	Exon 20 of 20	NP_000186.2
	HPS1	NM_001322476.2		c.*12C>T		3_prime_UTR	Exon 20 of 20	NP_001309405.1
	HPS1	NM_001322477.2		c.*12C>T		3_prime_UTR	Exon 20 of 20	NP_001309406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS1	ENST00000361490.9	TSL:1 MANE Select	c.*12C>T		3_prime_UTR	Exon 20 of 20	ENSP00000355310.4
	HPS1	ENST00000467246.5	TSL:1	n.*1474C>T		non_coding_transcript_exon	Exon 19 of 19	ENSP00000514163.1
	HPS1	ENST00000467246.5	TSL:1	n.*1474C>T		3_prime_UTR	Exon 19 of 19	ENSP00000514163.1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152128 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00294 AC: 712 AN: 242288 AF XY: 0.00273

Gnomad AFR exome AF: 0.000589

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00418 AC: 6083 AN: 1453778 Hom.: 18 Cov.: 31 AF XY: 0.00399 AC XY: 2886 AN XY: 722714

African (AFR) AF: 0.000570 AC: 19 AN: 33348

American (AMR) AF: 0.00183 AC: 81 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25920

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.000409 AC: 35 AN: 85654

European-Finnish (FIN) AF: 0.00257 AC: 134 AN: 52232

Middle Eastern (MID) AF: 0.000225 AC: 1 AN: 4444

European-Non Finnish (NFE) AF: 0.00508 AC: 5632 AN: 1108462

Other (OTH) AF: 0.00294 AC: 176 AN: 59910

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152246 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74438

African (AFR) AF: 0.00125 AC: 52 AN: 41564

American (AMR) AF: 0.00399 AC: 61 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 67986

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00334 Hom.: 0

Bravo AF: 0.00303

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.82
PhyloP100		-2.2
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: rs112544050; hg19: chr10-100177309;