rs201439984

Variant names:

• chr11-18298975-G-A
• rs201439984
• NM_181507.2:c.986-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-18298975-G-A
• chr11-18298975-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181507.2(HPS5):​c.986-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,613,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: HPS5 NM_181507.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002768
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.751

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-18298975-G-A is Benign according to our data. Variant chr11-18298975-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262990.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000447 (68/152284) while in subpopulation SAS AF= 0.00269 (13/4824). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS5	NM_181507.2	c.986-5C>T		splice_region_variant, intron_variant	Intron 9 of 22	ENST00000349215.8	NP_852608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS5	ENST00000349215.8	c.986-5C>T		splice_region_variant, intron_variant	Intron 9 of 22	1	NM_181507.2	ENSP00000265967.5
HPS5	ENST00000396253.7	c.644-5C>T		splice_region_variant, intron_variant	Intron 8 of 21	1		ENSP00000379552.3
HPS5	ENST00000438420.6	c.644-5C>T		splice_region_variant, intron_variant	Intron 8 of 21	1		ENSP00000399590.2
HPS5	ENST00000531848.1	c.644-5C>T		splice_region_variant, intron_variant	Intron 8 of 10	5		ENSP00000431758.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000776 AC: 195 AN: 251344 Hom.: 1 AF XY: 0.000810 AC XY: 110 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000424 AC: 620 AN: 1461610 Hom.: 2 Cov.: 31 AF XY: 0.000461 AC XY: 335 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00972

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74450

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000883 Hom.: 0

Bravo AF: 0.000450

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hermansky-Pudlak syndrome 5 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.018
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

Publications

LitVar

Other links and lift over

dbSNP: rs201439984; hg19: chr11-18320522;