11-18306101-T-G

Variant names:

• chr11-18306101-T-G
• rs7122032
• NM_181507.2:c.824+34A>C

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.824+34A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,434,014 control chromosomes in the GnomAD database, including 9,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1585 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8319 hom.)
• Consequence: HPS5 NM_181507.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.309
• Publications: 5 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 (BayesDel_noAF=-0.8).
• BP6: Variant 11-18306101-T-G is Benign according to our data. Variant chr11-18306101-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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.824+34A>C		intron	N/A	NP_852608.1
	HPS5	NM_001440902.1		c.824+34A>C		intron	N/A	NP_001427831.1
	HPS5	NM_001440903.1		c.824+34A>C		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.824+34A>C		intron	N/A	ENSP00000265967.5
	HPS5	ENST00000396253.7	TSL:1	c.482+34A>C		intron	N/A	ENSP00000379552.3
	HPS5	ENST00000438420.6	TSL:1	c.482+34A>C		intron	N/A	ENSP00000399590.2

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21213 AN: 152072 Hom.: 1582 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.137 AC: 34279 AN: 250790 AF XY: 0.131

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.107 AC: 136957 AN: 1281824 Hom.: 8319 Cov.: 19 AF XY: 0.107 AC XY: 69336 AN XY: 647048

African (AFR) AF: 0.191 AC: 5673 AN: 29672

American (AMR) AF: 0.205 AC: 9109 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 2992 AN: 25074

East Asian (EAS) AF: 0.153 AC: 5939 AN: 38762

South Asian (SAS) AF: 0.126 AC: 10366 AN: 82546

European-Finnish (FIN) AF: 0.159 AC: 8494 AN: 53332

Middle Eastern (MID) AF: 0.153 AC: 817 AN: 5332

European-Non Finnish (NFE) AF: 0.0922 AC: 87450 AN: 948286

Other (OTH) AF: 0.113 AC: 6117 AN: 54328

GnomAD4 genome AF: 0.139 AC: 21227 AN: 152190 Hom.: 1585 Cov.: 32 AF XY: 0.142 AC XY: 10603 AN XY: 74422

African (AFR) AF: 0.190 AC: 7893 AN: 41516

American (AMR) AF: 0.156 AC: 2390 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3470

East Asian (EAS) AF: 0.119 AC: 615 AN: 5178

South Asian (SAS) AF: 0.129 AC: 620 AN: 4820

European-Finnish (FIN) AF: 0.176 AC: 1861 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7011 AN: 68002

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.127 Hom.: 448

Bravo AF: 0.140

Asia WGS AF: 0.141 AC: 492 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.7
DANN	Benign	0.51
PhyloP100		0.31
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: rs7122032; hg19: chr11-18327648;