rs189953957

Variant names:

• chr22-26453436-A-G
• rs189953957
• NM_022081.6:c.1956-32T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022081.6(HPS4):​c.1956-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,611,714 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (102 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.33
• Publications: 0 publications found

Genes affected

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Hermansky-Pudlak syndrome with 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=-0.92).
• BP6: Variant 22-26453436-A-G is Benign according to our data. Variant chr22-26453436-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00735 (1120/152338) while in subpopulation NFE AF = 0.0112 (760/68036). AF 95% confidence interval is 0.0105. There are 8 homozygotes in GnomAd4. There are 571 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.1956-32T>C		intron_variant	Intron 13 of 13	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.1956-32T>C		intron_variant	Intron 13 of 13	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1119 AN: 152220 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00811 AC: 2039 AN: 251356 AF XY: 0.00838

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.0103 AC: 15057 AN: 1459376 Hom.: 102 Cov.: 30 AF XY: 0.0102 AC XY: 7427 AN XY: 726122

African (AFR) AF: 0.00177 AC: 59 AN: 33400

American (AMR) AF: 0.00364 AC: 163 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 181 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00556 AC: 479 AN: 86160

European-Finnish (FIN) AF: 0.0115 AC: 613 AN: 53414

Middle Eastern (MID) AF: 0.00262 AC: 12 AN: 4582

European-Non Finnish (NFE) AF: 0.0117 AC: 13011 AN: 1111030

Other (OTH) AF: 0.00893 AC: 538 AN: 60238

GnomAD4 genome AF: 0.00735 AC: 1120 AN: 152338 Hom.: 8 Cov.: 32 AF XY: 0.00766 AC XY: 571 AN XY: 74496

African (AFR) AF: 0.00159 AC: 66 AN: 41582

American (AMR) AF: 0.00647 AC: 99 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0112 AC: 760 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00771 Hom.: 1

Bravo AF: 0.00699

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0010
DANN	Benign	0.23
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism

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: rs189953957; hg19: chr22-26849402;