rs2049129

Variant names:

• chr11-18283786-T-C
• rs2049129
• NM_181507.2:c.3058+9A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-18283786-T-C
• chr11-18283786-T-A

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.3058+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,582,672 control chromosomes in the GnomAD database, including 25,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3241 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21959 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.526
• Publications: 12 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 (BayesDel_noAF=-0.66).
• BP6: Variant 11-18283786-T-C is Benign according to our data. Variant chr11-18283786-T-C is described in ClinVar as Benign. ClinVar VariationId is 163676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

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.3058+9A>G		intron	N/A	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.3058+9A>G		intron	N/A	NP_001427831.1
	HPS5	NM_001440903.1		c.3058+9A>G		intron	N/A	NP_001427832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.3058+9A>G		intron	N/A	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.2716+9A>G		intron	N/A	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.2716+9A>G		intron	N/A	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29327 AN: 151954 Hom.: 3236 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.147 AC: 36894 AN: 250774 AF XY: 0.145

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.169 AC: 241073 AN: 1430600 Hom.: 21959 Cov.: 26 AF XY: 0.166 AC XY: 118264 AN XY: 713432

African (AFR) AF: 0.296 AC: 9704 AN: 32824

American (AMR) AF: 0.0873 AC: 3900 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4233 AN: 25940

East Asian (EAS) AF: 0.000835 AC: 33 AN: 39532

South Asian (SAS) AF: 0.0775 AC: 6636 AN: 85670

European-Finnish (FIN) AF: 0.211 AC: 11102 AN: 52696

Middle Eastern (MID) AF: 0.184 AC: 1048 AN: 5692

European-Non Finnish (NFE) AF: 0.180 AC: 194824 AN: 1084134

Other (OTH) AF: 0.161 AC: 9593 AN: 59426

GnomAD4 genome AF: 0.193 AC: 29347 AN: 152072 Hom.: 3241 Cov.: 32 AF XY: 0.189 AC XY: 14039 AN XY: 74340

African (AFR) AF: 0.285 AC: 11814 AN: 41438

American (AMR) AF: 0.124 AC: 1898 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0604 AC: 291 AN: 4818

European-Finnish (FIN) AF: 0.203 AC: 2147 AN: 10582

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12146 AN: 67982

Other (OTH) AF: 0.173 AC: 366 AN: 2110

Alfa AF: 0.177 Hom.: 8160

Bravo AF: 0.190

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hermansky-Pudlak syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.7
DANN	Benign	0.82
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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: rs2049129; hg19: chr11-18305333; COSMIC: COSV61687578; COSMIC: COSV61687578;