rs3747129

Variant names:

• chr22-26466075-G-A
• rs3747129
• NM_022081.6:c.706+151C>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.706+151C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,567,474 control chromosomes in the GnomAD database, including 22,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1643 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20659 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 25 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 (BayesDel_addAF=-0.833905).
• BP6: Variant 22-26466075-G-A is Benign according to our data. Variant chr22-26466075-G-A is described in ClinVar as Benign. ClinVar VariationId is 1296784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.706+151C>T		intron_variant	Intron 9 of 13	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.706+151C>T		intron_variant	Intron 9 of 13	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18821 AN: 152036 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.173 AC: 33094 AN: 191268 AF XY: 0.188

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.160 AC: 226005 AN: 1415320 Hom.: 20659 Cov.: 31 AF XY: 0.167 AC XY: 116803 AN XY: 701058

African (AFR) AF: 0.0246 AC: 802 AN: 32626

American (AMR) AF: 0.108 AC: 4257 AN: 39262

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3899 AN: 25328

East Asian (EAS) AF: 0.226 AC: 8452 AN: 37402

South Asian (SAS) AF: 0.359 AC: 29084 AN: 81024

European-Finnish (FIN) AF: 0.191 AC: 8776 AN: 45982

Middle Eastern (MID) AF: 0.234 AC: 1332 AN: 5696

European-Non Finnish (NFE) AF: 0.147 AC: 159796 AN: 1089170

Other (OTH) AF: 0.163 AC: 9607 AN: 58830

GnomAD4 genome AF: 0.124 AC: 18837 AN: 152154 Hom.: 1643 Cov.: 32 AF XY: 0.130 AC XY: 9690 AN XY: 74364

African (AFR) AF: 0.0277 AC: 1152 AN: 41546

American (AMR) AF: 0.115 AC: 1763 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3470

East Asian (EAS) AF: 0.236 AC: 1220 AN: 5172

South Asian (SAS) AF: 0.359 AC: 1728 AN: 4808

European-Finnish (FIN) AF: 0.197 AC: 2086 AN: 10572

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9919 AN: 67998

Other (OTH) AF: 0.138 AC: 292 AN: 2112

Alfa AF: 0.143 Hom.: 5777

Bravo AF: 0.111

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.155 AC: 596

ExAC AF: 0.152 AC: 18017

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Uncertain	0.99
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.057	N
PhyloP100		-0.016
GERP RS		2.1
Mutation Taster		=135/65	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: rs3747129; hg19: chr22-26862041; COSMIC: COSV61102632; COSMIC: COSV61102632;