rs1894706

chr22-26458475-G-Achr22-26458475-G-C

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.1816C>T(p.His606Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.909 in 1,613,888 control chromosomes in the GnomAD database, including 670,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H606H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (57491 hom., cov: 30)
  • Exomes 𝑓: 0.91 (613157 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.06

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=9.1983E-6).
• BP6: Variant 22-26458475-G-A is Benign according to our data. Variant chr22-26458475-G-A is described in ClinVar as [Benign]. Clinvar id is 163671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26458475-G-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.1816C>T	p.His606Tyr	missense_variant	12/14	ENST00000398145.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS4	ENST00000398145.7	c.1816C>T	p.His606Tyr	missense_variant	12/14	1	NM_022081.6	P2

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131482 AN: 151944 Hom.: 57479 Cov.: 30

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.952

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.873

GnomAD3 exomes AF: 0.877 AC: 220435 AN: 251290 Hom.: 97959 AF XY: 0.890 AC XY: 120857 AN XY: 135826

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.959

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: 1336049 AN: 1461828 Hom.: 613157 Cov.: 61 AF XY: 0.916 AC XY: 666301 AN XY: 727212

Gnomad4 AFR exome AF: 0.750

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: 131542 AN: 152060 Hom.: 57491 Cov.: 30 AF XY: 0.865 AC XY: 64319 AN XY: 74332

Gnomad4 AFR AF: 0.754

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.952

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.914

Gnomad4 FIN AF: 0.982

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.870

Alfa AF: 0.915 Hom.: 162322

Bravo AF: 0.842

TwinsUK AF: 0.926 AC: 3433

ALSPAC AF: 0.921 AC: 3551

ESP6500AA AF: 0.754 AC: 3322

ESP6500EA AF: 0.928 AC: 7979

ExAC AF: 0.882 AC: 107045

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His606Tyr in exon 12 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 24.6% (1084/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs1894706). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	0.19
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0000092	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;M
MutationTaster	Benign	0.012	P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.052	T;T;T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.32
MPC		0.32
ClinPred		0.022	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs1894706; hg19: chr22-26854441; COSMIC: COSV61102886;