chr11-18279606-A-C

Variant names:

• chr11-18279606-A-C
• rs146958457
• NM_181507.2:c.*276T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_181507.2(HPS5):​c.*276T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 493,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: HPS5 NM_181507.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000459 (7/152372) while in subpopulation EAS AF = 0.00135 (7/5192). AF 95% confidence interval is 0.000632. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*276T>G		3_prime_UTR	Exon 23 of 23	NP_852608.1	Q9UPZ3-1
	HPS5	NM_001440902.1		c.*329T>G		3_prime_UTR	Exon 24 of 24	NP_001427831.1
	HPS5	NM_001440903.1		c.*329T>G		3_prime_UTR	Exon 24 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.*276T>G		3_prime_UTR	Exon 23 of 23	ENSP00000265967.5	Q9UPZ3-1
	HPS5	ENST00000396253.7	TSL:1	c.*276T>G		3_prime_UTR	Exon 22 of 22	ENSP00000379552.3	Q9UPZ3-2
	HPS5	ENST00000438420.6	TSL:1	c.*276T>G		3_prime_UTR	Exon 22 of 22	ENSP00000399590.2	Q9UPZ3-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 44 AN: 341224 Hom.: 0 Cov.: 0 AF XY: 0.000104 AC XY: 19 AN XY: 182454

African (AFR) AF: 0.00 AC: 0 AN: 9998

American (AMR) AF: 0.00 AC: 0 AN: 14336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10266

East Asian (EAS) AF: 0.00209 AC: 44 AN: 21004

South Asian (SAS) AF: 0.00 AC: 0 AN: 42086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 204150

Other (OTH) AF: 0.00 AC: 0 AN: 19232

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74512

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hermansky-Pudlak syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.46
PhyloP100		-0.039

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: rs146958457; hg19: chr11-18301153;