chr11-18295911-T-A

Variant names:

• chr11-18295911-T-A
• rs2305564
• NM_181507.2:c.1634+88A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181507.2(HPS5):​c.1634+88A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,383,236 control chromosomes in the GnomAD database, including 198,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17969 hom., cov: 32)
  • Exomes 𝑓: 0.54 (180508 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.166
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-18295911-T-A is Benign according to our data. Variant chr11-18295911-T-A is described in ClinVar as Benign. ClinVar VariationId is 1263434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.1634+88A>T		intron_variant	Intron 13 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.1634+88A>T		intron_variant	Intron 13 of 22	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72576 AN: 151934 Hom.: 17953 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.444

GnomAD4 exome AF: 0.537 AC: 661099 AN: 1231184 Hom.: 180508 AF XY: 0.533 AC XY: 332444 AN XY: 623718

African (AFR) AF: 0.342 AC: 9742 AN: 28508

American (AMR) AF: 0.510 AC: 22356 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9075 AN: 24602

East Asian (EAS) AF: 0.566 AC: 21637 AN: 38214

South Asian (SAS) AF: 0.464 AC: 37452 AN: 80738

European-Finnish (FIN) AF: 0.527 AC: 27262 AN: 51754

Middle Eastern (MID) AF: 0.303 AC: 1607 AN: 5304

European-Non Finnish (NFE) AF: 0.558 AC: 505143 AN: 905630

Other (OTH) AF: 0.510 AC: 26825 AN: 52588

GnomAD4 genome AF: 0.478 AC: 72638 AN: 152052 Hom.: 17969 Cov.: 32 AF XY: 0.477 AC XY: 35444 AN XY: 74310

African (AFR) AF: 0.354 AC: 14663 AN: 41464

American (AMR) AF: 0.498 AC: 7617 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1267 AN: 3464

East Asian (EAS) AF: 0.587 AC: 3036 AN: 5168

South Asian (SAS) AF: 0.489 AC: 2353 AN: 4810

European-Finnish (FIN) AF: 0.518 AC: 5455 AN: 10540

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36621 AN: 68002

Other (OTH) AF: 0.445 AC: 940 AN: 2112

Alfa AF: 0.499 Hom.: 2424

Bravo AF: 0.472

Asia WGS AF: 0.525 AC: 1825 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.17
PromoterAI		0.0034	Neutral
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: rs2305564; hg19: chr11-18317458; COSMIC: COSV61687995; COSMIC: COSV61687995;