22-26458014-T-C

Variant names:

• chr22-26458014-T-C
• rs1894705
• NM_022081.6:c.1847-47A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):​c.1847-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.923 in 1,452,274 control chromosomes in the GnomAD database, including 620,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59883 hom., cov: 34)
  • Exomes 𝑓: 0.93 (561099 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.17
• Publications: 9 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=-0.95).
• BP6: Variant 22-26458014-T-C is Benign according to our data. Variant chr22-26458014-T-C is described in ClinVar as Benign. ClinVar VariationId is 261533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	NM_022081.6	MANE Select	c.1847-47A>G		intron	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.1901-47A>G		intron	N/A	NP_001336829.1
	HPS4	NM_001349901.1		c.1901-47A>G		intron	N/A	NP_001336830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.1847-47A>G		intron	N/A	ENSP00000381213.2
	HPS4	ENST00000402105.7	TSL:1	c.1832-47A>G		intron	N/A	ENSP00000384185.3
	HPS4	ENST00000439453.5	TSL:1	n.*1365-47A>G		intron	N/A	ENSP00000406764.1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134353 AN: 152148 Hom.: 59867 Cov.: 34

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.964

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.945

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.890 AC: 188797 AN: 212160 AF XY: 0.902

Gnomad AFR exome AF: 0.770

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.970

Gnomad EAS exome AF: 0.853

Gnomad FIN exome AF: 0.986

Gnomad NFE exome AF: 0.943

Gnomad OTH exome AF: 0.915

GnomAD4 exome AF: 0.927 AC: 1205646 AN: 1300008 Hom.: 561099 Cov.: 18 AF XY: 0.930 AC XY: 607118 AN XY: 653134

African (AFR) AF: 0.769 AC: 23472 AN: 30526

American (AMR) AF: 0.711 AC: 29564 AN: 41564

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 24007 AN: 24802

East Asian (EAS) AF: 0.848 AC: 32502 AN: 38316

South Asian (SAS) AF: 0.934 AC: 75844 AN: 81232

European-Finnish (FIN) AF: 0.982 AC: 42559 AN: 43360

Middle Eastern (MID) AF: 0.930 AC: 4295 AN: 4620

European-Non Finnish (NFE) AF: 0.941 AC: 922652 AN: 980438

Other (OTH) AF: 0.920 AC: 50751 AN: 55150

GnomAD4 genome AF: 0.883 AC: 134420 AN: 152266 Hom.: 59883 Cov.: 34 AF XY: 0.883 AC XY: 65701 AN XY: 74446

African (AFR) AF: 0.777 AC: 32265 AN: 41532

American (AMR) AF: 0.799 AC: 12223 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.964 AC: 3348 AN: 3472

East Asian (EAS) AF: 0.852 AC: 4395 AN: 5158

South Asian (SAS) AF: 0.925 AC: 4470 AN: 4830

European-Finnish (FIN) AF: 0.989 AC: 10507 AN: 10626

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.945 AC: 64294 AN: 68022

Other (OTH) AF: 0.888 AC: 1877 AN: 2114

Alfa AF: 0.919 Hom.: 22028

Bravo AF: 0.862

Asia WGS AF: 0.859 AC: 2989 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.95
CADD	Benign	0.021
DANN	Benign	0.20
PhyloP100		-3.2
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: rs1894705; hg19: chr22-26853980;