11-18303599-C-T

Variant names:

• chr11-18303599-C-T
• rs2403254
• NM_181507.2:c.896+1823G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181507.2(HPS5):​c.896+1823G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,018 control chromosomes in the GnomAD database, including 15,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.42 (15783 hom., cov: 31)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.644
• Publications: 32 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.896+1823G>A		intron_variant	Intron 8 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.896+1823G>A		intron_variant	Intron 8 of 22	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253.7	c.554+1823G>A		intron_variant	Intron 7 of 21	1		ENSP00000379552.3
HPS5	ENST00000438420.6	c.554+1823G>A		intron_variant	Intron 7 of 21	1		ENSP00000399590.2
HPS5	ENST00000531848.1	c.554+1823G>A		intron_variant	Intron 7 of 10	5		ENSP00000431758.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64258 AN: 151900 Hom.: 15779 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.423 AC: 64276 AN: 152018 Hom.: 15783 Cov.: 31 AF XY: 0.424 AC XY: 31497 AN XY: 74286

African (AFR) AF: 0.160 AC: 6630 AN: 41492

American (AMR) AF: 0.480 AC: 7332 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1267 AN: 3466

East Asian (EAS) AF: 0.589 AC: 3041 AN: 5160

South Asian (SAS) AF: 0.489 AC: 2359 AN: 4820

European-Finnish (FIN) AF: 0.517 AC: 5452 AN: 10536

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36639 AN: 67960

Other (OTH) AF: 0.413 AC: 871 AN: 2108

Alfa AF: 0.486 Hom.: 66433

Bravo AF: 0.408

Asia WGS AF: 0.515 AC: 1788 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

decreased blood alpha-hydroxyisovalerate levels Other:1

May 11, 2014

Human Genetics, Leiden University Medical Centre

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.9
DANN	Benign	0.87
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs2403254; hg19: chr11-18325146;