rs3747129

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

1
6

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0160
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_addAF=-0.833905).
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/exons MANE Protein UniProt
HPS4NM_022081.6 linkuse as main transcriptc.706+151C>T intron_variant ENST00000398145.7 NP_071364.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HPS4ENST00000398145.7 linkuse as main transcriptc.706+151C>T intron_variant 1 NM_022081.6 ENSP00000381213 P2Q9NQG7-1

Frequencies

GnomAD3 genomes
AF:
0.124
AC:
18821
AN:
152036
Hom.:
1638
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.173
AC:
33094
AN:
191268
Hom.:
3600
AF XY:
0.188
AC XY:
19282
AN XY:
102368
show subpopulations
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 SAS exome
AF:
0.362
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0246
Gnomad4 AMR exome
AF:
0.108
Gnomad4 ASJ exome
AF:
0.154
Gnomad4 EAS exome
AF:
0.226
Gnomad4 SAS exome
AF:
0.359
Gnomad4 FIN exome
AF:
0.191
Gnomad4 NFE exome
AF:
0.147
Gnomad4 OTH exome
AF:
0.163
GnomAD4 genome
AF:
0.124
AC:
18837
AN:
152154
Hom.:
1643
Cov.:
32
AF XY:
0.130
AC XY:
9690
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0277
Gnomad4 AMR
AF:
0.115
Gnomad4 ASJ
AF:
0.147
Gnomad4 EAS
AF:
0.236
Gnomad4 SAS
AF:
0.359
Gnomad4 FIN
AF:
0.197
Gnomad4 NFE
AF:
0.146
Gnomad4 OTH
AF:
0.138
Alfa
AF:
0.151
Hom.:
3732
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
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018- -

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
MutationTaster
Benign
7.9e-18
P;P;P;P
GERP RS
2.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3747129; hg19: chr22-26862041; COSMIC: COSV61102632; COSMIC: COSV61102632; API