rs186991064

chr11-18305509-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_181507.2(HPS5):c.825-16T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

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]

ACMG classification

Verdict is Benign. Variant got -16 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. Variant chr11-18305509-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2	c.825-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8	c.825-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_181507.2	P1
HPS5	ENST00000396253.7	c.483-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1
HPS5	ENST00000438420.6	c.483-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1
HPS5	ENST00000531848.1	c.483-16T>C		splice_polypyrimidine_tract_variant, intron_variant		5

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

GnomAD3 exomes AF: 0.00133 AC: 334 AN: 250618 Hom.: 2 AF XY: 0.00129 AC XY: 175 AN XY: 135450

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 SAS exome AF: 0.000427

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

Gnomad4 AFR exome AF: 0.000280

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000495

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00247

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

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00189

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	2.1
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs186991064; hg19: chr11-18327056;