rs9625029

Variant names:

• chr22-26453398-G-A
• rs9625029
• NM_022081.6:c.1962C>T

Variant summary

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

The NM_001349902.1(HPS4):​c.1720C>T​(p.Leu574Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,944 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L574L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: HPS4 NM_001349902.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.39
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, 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=-0.48).
• BP6: Variant 22-26453398-G-A is Benign according to our data. Variant chr22-26453398-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261535.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 = 0.00801 (1221/152344) while in subpopulation NFE AF = 0.0129 (877/68036). AF 95% confidence interval is 0.0122. There are 10 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349902.1. 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
	HPS4	NM_022081.6	MANE Select	c.1962C>T	p.Ala654Ala	synonymous	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349902.1		c.1720C>T	p.Leu574Phe	missense	Exon 12 of 12	NP_001336831.1	A0A8V8TMY3
	HPS4	NM_001349903.2		c.1720C>T	p.Leu574Phe	missense	Exon 12 of 12	NP_001336832.1	A0A8V8TMY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.1962C>T	p.Ala654Ala	synonymous	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.1947C>T	p.Ala649Ala	synonymous	Exon 12 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*1480C>T		non_coding_transcript_exon	Exon 14 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1220 AN: 152226 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00808 AC: 2031 AN: 251492 AF XY: 0.00823

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0113 AC: 16460 AN: 1461600 Hom.: 103 Cov.: 31 AF XY: 0.0110 AC XY: 8015 AN XY: 727092

African (AFR) AF: 0.00245 AC: 82 AN: 33476

American (AMR) AF: 0.00724 AC: 324 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00804 AC: 210 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86242

European-Finnish (FIN) AF: 0.00417 AC: 223 AN: 53420

Middle Eastern (MID) AF: 0.0216 AC: 120 AN: 5558

European-Non Finnish (NFE) AF: 0.0132 AC: 14682 AN: 1111972

Other (OTH) AF: 0.0106 AC: 638 AN: 60374

GnomAD4 genome AF: 0.00801 AC: 1221 AN: 152344 Hom.: 10 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74490

African (AFR) AF: 0.00253 AC: 105 AN: 41580

American (AMR) AF: 0.00902 AC: 138 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 877 AN: 68036

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0115 Hom.: 19

Bravo AF: 0.00872

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.8
DANN	Benign	0.42
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs9625029; hg19: chr22-26849364;