rs73432728

Variant names:

• chr11-18311994-A-G
• rs73432728
• ENST00000396253.7:c.-204T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001440920.1(HPS5):​c.-204T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,613,970 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (76 hom.)
• Consequence: HPS5 NM_001440920.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.261
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-18311994-A-G is Benign according to our data. Variant chr11-18311994-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440920.1. 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.139T>C	p.Leu47Leu	synonymous	Exon 3 of 23	NP_852608.1
	HPS5	NM_001440920.1		c.-204T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001427849.1
	HPS5	NM_001440921.1		c.-204T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001427850.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS5	ENST00000396253.7	TSL:1	c.-204T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.-204T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	ENSP00000399590.2
	HPS5	ENST00000349215.8	TSL:1 MANE Select	c.139T>C	p.Leu47Leu	synonymous	Exon 3 of 23	ENSP00000265967.5

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2948 AN: 152140 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00504 AC: 1267 AN: 251404 AF XY: 0.00339

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00187 AC: 2732 AN: 1461712 Hom.: 76 Cov.: 30 AF XY: 0.00157 AC XY: 1145 AN XY: 727180

African (AFR) AF: 0.0671 AC: 2245 AN: 33452

American (AMR) AF: 0.00376 AC: 168 AN: 44720

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111902

Other (OTH) AF: 0.00421 AC: 254 AN: 60388

GnomAD4 genome AF: 0.0194 AC: 2956 AN: 152258 Hom.: 102 Cov.: 32 AF XY: 0.0187 AC XY: 1395 AN XY: 74462

African (AFR) AF: 0.0678 AC: 2817 AN: 41526

American (AMR) AF: 0.00680 AC: 104 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00883 Hom.: 23

Bravo AF: 0.0226

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.31
CADD	Benign	5.3
DANN	Benign	0.80
PhyloP100		0.26
Mutation Taster		=92/8	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: rs73432728; hg19: chr11-18333541;