11-18306137-G-T

Position:

• chr11-18306137-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000349215.8(HPS5):​c.822C>A​(p.Leu274=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,597,472 control chromosomes in the GnomAD database, including 410,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40614 hom., cov: 32)
  • Exomes 𝑓: 0.71 (370185 hom.)
• Consequence: HPS5 ENST00000349215.8 splice_region, synonymous
• Scores: Splicing: ADA: 0.00007983
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.30

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-18306137-G-T is Benign according to our data. Variant chr11-18306137-G-T is described in ClinVar as [Benign]. Clinvar id is 163678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-18306137-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPS5	NM_181507.2	c.822C>A	p.Leu274=	splice_region_variant, synonymous_variant	7/23	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.822C>A	p.Leu274=	splice_region_variant, synonymous_variant	7/23	1	NM_181507.2	ENSP00000265967	P1
HPS5	ENST00000396253.7	c.480C>A	p.Leu160=	splice_region_variant, synonymous_variant	6/22	1		ENSP00000379552
HPS5	ENST00000438420.6	c.480C>A	p.Leu160=	splice_region_variant, synonymous_variant	6/22	1		ENSP00000399590
HPS5	ENST00000531848.1	c.480C>A	p.Leu160=	splice_region_variant, synonymous_variant	6/11	5		ENSP00000431758

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110426 AN: 151934 Hom.: 40566 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.711

GnomAD3 exomes AF: 0.732 AC: 183949 AN: 251348 Hom.: 68406 AF XY: 0.723 AC XY: 98173 AN XY: 135842

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.976

Gnomad SAS exome AF: 0.726

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.713 AC: 1030552 AN: 1445420 Hom.: 370185 Cov.: 29 AF XY: 0.711 AC XY: 511979 AN XY: 720278

Gnomad4 AFR exome AF: 0.760

Gnomad4 AMR exome AF: 0.803

Gnomad4 ASJ exome AF: 0.581

Gnomad4 EAS exome AF: 0.962

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.713

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.712

GnomAD4 genome AF: 0.727 AC: 110530 AN: 152052 Hom.: 40614 Cov.: 32 AF XY: 0.730 AC XY: 54286 AN XY: 74334

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.746

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.969

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.689

Gnomad4 OTH AF: 0.714

Alfa AF: 0.692 Hom.: 56005

Bravo AF: 0.733

Asia WGS AF: 0.888 AC: 3084 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.671

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hermansky-Pudlak syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.0
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.022
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

Publications

LitVar

Other links and lift over

dbSNP: rs1140047; hg19: chr11-18327684;