rs186991064

Variant names:

• chr11-18305509-A-G
• rs186991064
• NM_181507.2:c.825-16T>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_181507.2(HPS5):​c.825-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,556,020 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50
• Publications: 0 publications found

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This 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 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Hermansky-Pudlak syndrome without pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-18305509-A-G is Benign according to our data. Variant chr11-18305509-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00106 (162/152288) while in subpopulation AMR AF = 0.00118 (18/15298). AF 95% confidence interval is 0.000928. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.825-16T>C		intron_variant	Intron 7 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.825-16T>C		intron_variant	Intron 7 of 22	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253.7	c.483-16T>C		intron_variant	Intron 6 of 21	1		ENSP00000379552.3
HPS5	ENST00000438420.6	c.483-16T>C		intron_variant	Intron 6 of 21	1		ENSP00000399590.2
HPS5	ENST00000531848.1	c.483-16T>C		intron_variant	Intron 6 of 10	5		ENSP00000431758.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00133 AC: 334 AN: 250618 AF XY: 0.00129

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00146 AC: 2051 AN: 1403732 Hom.: 3 Cov.: 23 AF XY: 0.00143 AC XY: 1003 AN XY: 701952

African (AFR) AF: 0.000280 AC: 9 AN: 32190

American (AMR) AF: 0.00141 AC: 63 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 348 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.000495 AC: 42 AN: 84874

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53158

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5658

European-Non Finnish (NFE) AF: 0.00135 AC: 1435 AN: 1059800

Other (OTH) AF: 0.00247 AC: 144 AN: 58348

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74472

African (AFR) AF: 0.000168 AC: 7 AN: 41552

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00106

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.1
DANN	Benign	0.74
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs186991064; hg19: chr11-18327056;