rs2014410

Variant names:

• chr22-26464303-G-C
• rs2014410
• NM_022081.6:c.1327C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-26464303-G-C
• chr22-26464303-G-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.1327C>G​(p.Leu443Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,613,716 control chromosomes in the GnomAD database, including 130,543 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L443L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10143 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120400 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.782
• Publications: 39 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=5.2847725E-5).
• BP6: Variant 22-26464303-G-C is Benign according to our data. Variant chr22-26464303-G-C is described in ClinVar as Benign. ClinVar VariationId is 163673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.1327C>G	p.Leu443Val	missense_variant	Exon 11 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.1327C>G	p.Leu443Val	missense_variant	Exon 11 of 14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54486 AN: 151876 Hom.: 10130 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.372 AC: 93288 AN: 250926 AF XY: 0.387

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.402 AC: 587687 AN: 1461722 Hom.: 120400 Cov.: 73 AF XY: 0.407 AC XY: 295635 AN XY: 727152

African (AFR) AF: 0.313 AC: 10477 AN: 33480

American (AMR) AF: 0.228 AC: 10189 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8102 AN: 26136

East Asian (EAS) AF: 0.288 AC: 11422 AN: 39698

South Asian (SAS) AF: 0.515 AC: 44464 AN: 86256

European-Finnish (FIN) AF: 0.367 AC: 19536 AN: 53276

Middle Eastern (MID) AF: 0.415 AC: 2395 AN: 5768

European-Non Finnish (NFE) AF: 0.412 AC: 457598 AN: 1111990

Other (OTH) AF: 0.389 AC: 23504 AN: 60394

GnomAD4 genome AF: 0.359 AC: 54527 AN: 151994 Hom.: 10143 Cov.: 32 AF XY: 0.356 AC XY: 26476 AN XY: 74276

African (AFR) AF: 0.308 AC: 12757 AN: 41482

American (AMR) AF: 0.275 AC: 4196 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3468

East Asian (EAS) AF: 0.297 AC: 1526 AN: 5136

South Asian (SAS) AF: 0.503 AC: 2422 AN: 4812

European-Finnish (FIN) AF: 0.365 AC: 3861 AN: 10578

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27562 AN: 67936

Other (OTH) AF: 0.347 AC: 732 AN: 2112

Alfa AF: 0.394 Hom.: 9074

Bravo AF: 0.349

TwinsUK AF: 0.405 AC: 1502

ALSPAC AF: 0.412 AC: 1586

ESP6500AA AF: 0.313 AC: 1381

ESP6500EA AF: 0.411 AC: 3536

ExAC AF: 0.383 AC: 46470

Asia WGS AF: 0.373 AC: 1299 AN: 3478

EpiCase AF: 0.404

EpiControl AF: 0.403

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu443Val in exon 11 of HPS4: This variant is not expected to have clinical sign ificance because it has been identified in 41.1% (3536/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2014410). -

-

PreventionGenetics, part of Exact Sciences

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

- -

Hermansky-Pudlak syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.079
DANN	Benign	0.45
DEOGEN2	Benign	0.10	T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.15	.;T;T;T
MetaRNN	Benign	0.000053	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;.
PhyloP100		-0.78
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.53	N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.69	T;T;T;T
Sift4G	Benign	0.51	T;T;T;.
Polyphen		0.19	B;B;B;.
Vest4		0.029
MPC		0.049
ClinPred		0.0014	T
GERP RS		-3.8
Varity_R		0.013
gMVP		0.16
Mutation Taster		=99/1	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: rs2014410; hg19: chr22-26860269; COSMIC: COSV61102518; COSMIC: COSV61102518;