NM_022081.6:c.1816C>T

Variant names:

• chr22-26458475-G-A
• rs1894706
• NM_022081.6:c.1816C>T

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.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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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:8
• Conservation: PhyloP100: 8.06
• Publications: 40 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 (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 VariationId is 163671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.1816C>T	p.His606Tyr	missense_variant	Exon 12 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.1816C>T	p.His606Tyr	missense_variant	Exon 12 of 14	1	NM_022081.6	ENSP00000381213.2

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

GnomAD2 exomes AF: 0.877 AC: 220435 AN: 251290 AF XY: 0.890

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 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

African (AFR) AF: 0.750 AC: 25113 AN: 33476

American (AMR) AF: 0.698 AC: 31237 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.957 AC: 25021 AN: 26136

East Asian (EAS) AF: 0.769 AC: 30514 AN: 39696

South Asian (SAS) AF: 0.927 AC: 79932 AN: 86258

European-Finnish (FIN) AF: 0.973 AC: 51996 AN: 53420

Middle Eastern (MID) AF: 0.913 AC: 5265 AN: 5766

European-Non Finnish (NFE) AF: 0.928 AC: 1032235 AN: 1111960

Other (OTH) AF: 0.906 AC: 54736 AN: 60392

GnomAD4 genome AF: 0.865 AC: 131542 AN: 152060 Hom.: 57491 Cov.: 30 AF XY: 0.865 AC XY: 64319 AN XY: 74332

African (AFR) AF: 0.754 AC: 31237 AN: 41420

American (AMR) AF: 0.785 AC: 11983 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.952 AC: 3305 AN: 3470

East Asian (EAS) AF: 0.786 AC: 4050 AN: 5152

South Asian (SAS) AF: 0.914 AC: 4407 AN: 4822

European-Finnish (FIN) AF: 0.982 AC: 10411 AN: 10604

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63279 AN: 68006

Other (OTH) AF: 0.870 AC: 1838 AN: 2112

Alfa AF: 0.904 Hom.: 240681

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hermansky-Pudlak syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome 4 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
LIST_S2	Benign	0.67	.;T;T
MetaRNN	Benign	0.0000092	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;M
PhyloP100		8.1
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
Mutation Taster		=96/4	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: rs1894706; hg19: chr22-26854441; COSMIC: COSV61102886;