rs61884288

Variant names:

• chr11-18281986-G-A
• rs61884288
• NM_181507.2:c.3293C>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_001440902.1(HPS5):​c.3293C>T​(p.Thr1098Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0331 in 1,614,064 control chromosomes in the GnomAD database, including 1,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (57 hom., cov: 32)
  • Exomes 𝑓: 0.034 (966 hom.)
• Consequence: HPS5 NM_001440902.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.18
• Publications: 16 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 (MetaRNN=0.0136913955).
• BP6: Variant 11-18281986-G-A is Benign according to our data. Variant chr11-18281986-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21821.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 = 0.0236 (3590/152242) while in subpopulation NFE AF = 0.0387 (2634/68022). AF 95% confidence interval is 0.0375. There are 57 homozygotes in GnomAd4. There are 1579 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440902.1. 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.3293C>T	p.Thr1098Ile	missense	Exon 22 of 23	NP_852608.1
	HPS5	NM_001440902.1		c.3293C>T	p.Thr1098Ile	missense	Exon 22 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.3293C>T	p.Thr1098Ile	missense	Exon 22 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.3293C>T	p.Thr1098Ile	missense	Exon 22 of 23	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.2951C>T	p.Thr984Ile	missense	Exon 21 of 22	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.2951C>T	p.Thr984Ile	missense	Exon 21 of 22	ENSP00000399590.2

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3591 AN: 152124 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0387

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0237 AC: 5954 AN: 251468 AF XY: 0.0235

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0372

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0341 AC: 49878 AN: 1461822 Hom.: 966 Cov.: 33 AF XY: 0.0334 AC XY: 24264 AN XY: 727210

African (AFR) AF: 0.00490 AC: 164 AN: 33480

American (AMR) AF: 0.0152 AC: 680 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 1066 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00741 AC: 639 AN: 86256

European-Finnish (FIN) AF: 0.0176 AC: 939 AN: 53420

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0401 AC: 44567 AN: 1111942

Other (OTH) AF: 0.0286 AC: 1729 AN: 60396

GnomAD4 genome AF: 0.0236 AC: 3590 AN: 152242 Hom.: 57 Cov.: 32 AF XY: 0.0212 AC XY: 1579 AN XY: 74446

African (AFR) AF: 0.00705 AC: 293 AN: 41534

American (AMR) AF: 0.0180 AC: 275 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0387 AC: 2634 AN: 68022

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

Alfa AF: 0.0333 Hom.: 341

Bravo AF: 0.0229

TwinsUK AF: 0.0391 AC: 145

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.00773 AC: 34

ESP6500EA AF: 0.0373 AC: 320

ExAC AF: 0.0236 AC: 2868

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0369

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Hermansky-Pudlak syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.2
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.045
Sift	Benign	0.29	T
Sift4G	Benign	0.14	T
Polyphen		0.46	P
Vest4		0.49
MPC		0.057
ClinPred		0.012	T
GERP RS		3.9
Varity_R		0.022
gMVP		0.21
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: rs61884288; hg19: chr11-18303533; COSMIC: COSV61687117; COSMIC: COSV61687117;