11-18291852-TTAAC-T

Variant names:

• chr11-18291852-TTAAC-T
• rs281865103
• NM_181507.2:c.2026_2029delGTTA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_181507.2(HPS5):​c.2026_2029delGTTA​(p.Val676MetfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V676V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPS5 NM_181507.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.235
• Publications: 2 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-18291852-TTAAC-T is Pathogenic according to our data. Variant chr11-18291852-TTAAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3152.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.2026_2029delGTTA	p.Val676MetfsTer8	frameshift	Exon 16 of 23	NP_852608.1
	HPS5	NM_001440902.1		c.2026_2029delGTTA	p.Val676MetfsTer8	frameshift	Exon 16 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.2026_2029delGTTA	p.Val676MetfsTer8	frameshift	Exon 16 of 24	NP_001427832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.2026_2029delGTTA	p.Val676MetfsTer8	frameshift	Exon 16 of 23	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.1684_1687delGTTA	p.Val562MetfsTer8	frameshift	Exon 15 of 22	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.1684_1687delGTTA	p.Val562MetfsTer8	frameshift	Exon 15 of 22	ENSP00000399590.2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Pathogenic:1

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281865103; hg19: chr11-18313399;