11-18322147-G-T

Variant names:

• chr11-18322147-G-T
• rs4150530
• ENST00000396253.7:c.-436C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181508.1(HPS5):​c.-249C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,328 control chromosomes in the GnomAD database, including 1,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1554 hom., cov: 32)
  • Exomes 𝑓: 0.067 (1 hom.)
• Consequence: HPS5 NM_181508.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.29

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]

GTF2H1 (HGNC:4655): (general transcription factor IIH subunit 1) Enables thyroid hormone receptor binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor TFIIH core complex and transcription factor TFIIH holo complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-18322147-G-T is Benign according to our data. Variant chr11-18322147-G-T is described in ClinVar as [Benign]. Clinvar id is 303906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.-251C>A		upstream_gene_variant		ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.-251C>A		upstream_gene_variant		1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20937 AN: 152030 Hom.: 1551 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.0667 AC: 12 AN: 180 Hom.: 1 Cov.: 0 AF XY: 0.0870 AC XY: 12 AN XY: 138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0455

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome AF: 0.138 AC: 20949 AN: 152148 Hom.: 1554 Cov.: 32 AF XY: 0.140 AC XY: 10440 AN XY: 74372

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.147

Alfa AF: 0.108 Hom.: 823

Bravo AF: 0.139

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs4150530; hg19: chr11-18343694;