rs143784823

Variant names:

• chr11-18296807-C-T
• rs143784823
• NM_181507.2:c.1501G>A

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.1501G>A​(p.Gly501Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,972 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. G501G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (31 hom.)
• Consequence: HPS5 NM_181507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.517
• Publications: 7 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=0.0039352775).
• BP6: Variant 11-18296807-C-T is Benign according to our data. Variant chr11-18296807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 303888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00399 (607/152236) while in subpopulation NFE AF = 0.00518 (352/68010). AF 95% confidence interval is 0.00473. There are 5 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1501G>A	p.Gly501Arg	missense	Exon 12 of 23	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.1501G>A	p.Gly501Arg	missense	Exon 12 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.1501G>A	p.Gly501Arg	missense	Exon 12 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.1501G>A	p.Gly501Arg	missense	Exon 12 of 23	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.1159G>A	p.Gly387Arg	missense	Exon 11 of 22	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.1159G>A	p.Gly387Arg	missense	Exon 11 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 606 AN: 152118 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00443 AC: 1113 AN: 251342 AF XY: 0.00448

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00329 AC: 4811 AN: 1461736 Hom.: 31 Cov.: 31 AF XY: 0.00349 AC XY: 2539 AN XY: 727206

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86254

European-Finnish (FIN) AF: 0.0202 AC: 1081 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00306 AC: 3399 AN: 1111874

Other (OTH) AF: 0.00247 AC: 149 AN: 60386

GnomAD4 genome AF: 0.00399 AC: 607 AN: 152236 Hom.: 5 Cov.: 32 AF XY: 0.00451 AC XY: 336 AN XY: 74444

African (AFR) AF: 0.000265 AC: 11 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.0208 AC: 220 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00518 AC: 352 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00397 Hom.: 5

Bravo AF: 0.00206

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00373 AC: 32

ExAC AF: 0.00441 AC: 535

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Hermansky-Pudlak syndrome 5 (1)
-	-	1	HPS5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.34
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.52
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.028
Sift	Benign	0.66	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.14		Gain of phosphorylation at S499 (P = 0.1251)
MVP		0.34
MPC		0.060
ClinPred		0.00056	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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: rs143784823; hg19: chr11-18318354;