rs4757638

Variant names:

• chr11-18291406-G-A
• rs4757638
• NM_181507.2:c.2440+36C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-18291406-G-A
• chr11-18291406-G-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.2440+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,365,908 control chromosomes in the GnomAD database, including 250,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26475 hom., cov: 31)
  • Exomes 𝑓: 0.60 (224162 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.19
• Publications: 21 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=-0.94).
• BP6: Variant 11-18291406-G-A is Benign according to our data. Variant chr11-18291406-G-A is described in ClinVar as Benign. ClinVar VariationId is 262985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.2440+36C>T		intron_variant	Intron 16 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.2440+36C>T		intron_variant	Intron 16 of 22	1	NM_181507.2	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89041 AN: 151648 Hom.: 26439 Cov.: 31

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.560

GnomAD2 exomes AF: 0.591 AC: 125786 AN: 212722 AF XY: 0.588

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.548

GnomAD4 exome AF: 0.604 AC: 733588 AN: 1214142 Hom.: 224162 Cov.: 16 AF XY: 0.602 AC XY: 368782 AN XY: 613054

African (AFR) AF: 0.567 AC: 15960 AN: 28146

American (AMR) AF: 0.596 AC: 24122 AN: 40504

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 11141 AN: 24216

East Asian (EAS) AF: 0.807 AC: 30441 AN: 37722

South Asian (SAS) AF: 0.593 AC: 45833 AN: 77242

European-Finnish (FIN) AF: 0.553 AC: 28852 AN: 52202

Middle Eastern (MID) AF: 0.388 AC: 1983 AN: 5116

European-Non Finnish (NFE) AF: 0.607 AC: 544274 AN: 896992

Other (OTH) AF: 0.596 AC: 30982 AN: 52002

GnomAD4 genome AF: 0.587 AC: 89130 AN: 151766 Hom.: 26475 Cov.: 31 AF XY: 0.588 AC XY: 43581 AN XY: 74124

African (AFR) AF: 0.575 AC: 23754 AN: 41344

American (AMR) AF: 0.589 AC: 8985 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1619 AN: 3470

East Asian (EAS) AF: 0.850 AC: 4389 AN: 5166

South Asian (SAS) AF: 0.621 AC: 2989 AN: 4812

European-Finnish (FIN) AF: 0.546 AC: 5712 AN: 10466

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.585 AC: 39720 AN: 67944

Other (OTH) AF: 0.565 AC: 1186 AN: 2100

Alfa AF: 0.570 Hom.: 45674

Bravo AF: 0.592

Asia WGS AF: 0.746 AC: 2589 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.94
CADD	Benign	0.053
DANN	Benign	0.75
PhyloP100		-3.2
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: rs4757638; hg19: chr11-18312953;