rs1894704

chr22-26457939-C-Achr22-26457939-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022081.6(HPS4):c.1875G>T(p.Gln625His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.909 in 1,613,816 control chromosomes in the GnomAD database, including 670,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57534 hom., cov: 33)
  • Exomes 𝑓: 0.91 (613039 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.3816076E-7).
• BP6: Variant 22-26457939-C-A is Benign according to our data. Variant chr22-26457939-C-A is described in ClinVar as [Benign]. Clinvar id is 163670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26457939-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS4	NM_022081.6	c.1875G>T	p.Gln625His	missense_variant	13/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.1875G>T	p.Gln625His	missense_variant	13/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131601 AN: 152140 Hom.: 57522 Cov.: 33

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.872

GnomAD3 exomes AF: 0.877 AC: 220034 AN: 250860 Hom.: 97766 AF XY: 0.890 AC XY: 120718 AN XY: 135666

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.960

Gnomad EAS exome AF: 0.793

Gnomad SAS exome AF: 0.922

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.914 AC: 1335791 AN: 1461558 Hom.: 613039 Cov.: 53 AF XY: 0.916 AC XY: 666194 AN XY: 727092

Gnomad4 AFR exome AF: 0.749

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.957

Gnomad4 EAS exome AF: 0.769

Gnomad4 SAS exome AF: 0.927

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.928

Gnomad4 OTH exome AF: 0.906

GnomAD4 genome AF: 0.865 AC: 131662 AN: 152258 Hom.: 57534 Cov.: 33 AF XY: 0.865 AC XY: 64394 AN XY: 74456

Gnomad4 AFR AF: 0.753

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.952

Gnomad4 EAS AF: 0.787

Gnomad4 SAS AF: 0.914

Gnomad4 FIN AF: 0.982

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.870

Alfa AF: 0.915 Hom.: 154897

Bravo AF: 0.842

TwinsUK AF: 0.926 AC: 3432

ALSPAC AF: 0.922 AC: 3552

ESP6500AA AF: 0.753 AC: 3317

ESP6500EA AF: 0.928 AC: 7979

ExAC AF: 0.881 AC: 107017

Asia WGS AF: 0.824 AC: 2868 AN: 3478

EpiCase AF: 0.932

EpiControl AF: 0.926

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gln625His in exon 13 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 24.7% (1089/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1894704). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Hermansky-Pudlak syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Hermansky-Pudlak syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	8.4e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;M
MutationTaster	Benign	0.85	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.83	P;P;P
Vest4		0.11
MutPred		0.16		Loss of helix (P = 0.0626);.;Loss of helix (P = 0.0626);
MPC		0.18
ClinPred		0.012	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1894704; hg19: chr22-26853905; COSMIC: COSV61105132;