11-18287917-G-A

Variant names:

• chr11-18287917-G-A
• rs144875223
• NM_181507.2:c.2537C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181507.2(HPS5):​c.2537C>T​(p.Pro846Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,613,920 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P846P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.84
• Publications: 5 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, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.008291066).
• BP6: Variant 11-18287917-G-A is Benign according to our data. Variant chr11-18287917-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 303874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00315 (480/152166) while in subpopulation AMR AF = 0.0282 (431/15288). AF 95% confidence interval is 0.026. There are 11 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	NM_181507.2	MANE Select	c.2537C>T	p.Pro846Leu	missense	Exon 17 of 23	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.2537C>T	p.Pro846Leu	missense	Exon 17 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.2537C>T	p.Pro846Leu	missense	Exon 17 of 24	NP_001427832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.2537C>T	p.Pro846Leu	missense	Exon 17 of 23	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.2195C>T	p.Pro732Leu	missense	Exon 16 of 22	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.2195C>T	p.Pro732Leu	missense	Exon 16 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152048 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00478 AC: 1201 AN: 251338 AF XY: 0.00375

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00119 AC: 1736 AN: 1461754 Hom.: 32 Cov.: 32 AF XY: 0.00103 AC XY: 747 AN XY: 727172

African (AFR) AF: 0.000538 AC: 18 AN: 33474

American (AMR) AF: 0.0337 AC: 1506 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39666

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111954

Other (OTH) AF: 0.00220 AC: 133 AN: 60390

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152166 Hom.: 11 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74382

African (AFR) AF: 0.000482 AC: 20 AN: 41520

American (AMR) AF: 0.0282 AC: 431 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.000890 Hom.: 6

Bravo AF: 0.00637

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00336 AC: 408

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hermansky-Pudlak syndrome 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.91
MPC		0.33
ClinPred		0.035	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.69
Mutation Taster		=92/8	polymorphism

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: rs144875223; hg19: chr11-18309464;