NM_022081.6:c.-253C>T

Variant names:

• chr22-26482015-G-A
• rs3747134
• NM_022081.6:c.-253C>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.-253C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 513,228 control chromosomes in the GnomAD database, including 189,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51305 hom., cov: 33)
  • Exomes 𝑓: 0.87 (137734 hom.)
• Consequence: HPS4 NM_022081.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.340
• Publications: 15 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_noAF=-0.79).
• BP6: Variant 22-26482015-G-A is Benign according to our data. Variant chr22-26482015-G-A is described in ClinVar as Benign. ClinVar VariationId is 341028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPS4	NM_022081.6	c.-253C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 14	ENST00000398145.7	NP_071364.4
HPS4	NM_022081.6	c.-253C>T		5_prime_UTR_variant	Exon 2 of 14	ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPS4	ENST00000398145.7	c.-253C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 14	1	NM_022081.6	ENSP00000381213.2
HPS4	ENST00000398145.7	c.-253C>T		5_prime_UTR_variant	Exon 2 of 14	1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123998 AN: 152056 Hom.: 51298 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.823

GnomAD4 exome AF: 0.871 AC: 314475 AN: 361052 Hom.: 137734 Cov.: 3 AF XY: 0.876 AC XY: 168117 AN XY: 191974

African (AFR) AF: 0.678 AC: 6952 AN: 10252

American (AMR) AF: 0.706 AC: 10973 AN: 15534

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 9170 AN: 10754

East Asian (EAS) AF: 0.769 AC: 17443 AN: 22696

South Asian (SAS) AF: 0.907 AC: 38952 AN: 42930

European-Finnish (FIN) AF: 0.945 AC: 20817 AN: 22026

Middle Eastern (MID) AF: 0.895 AC: 1357 AN: 1516

European-Non Finnish (NFE) AF: 0.890 AC: 191346 AN: 215064

Other (OTH) AF: 0.861 AC: 17465 AN: 20280

GnomAD4 genome AF: 0.815 AC: 124053 AN: 152176 Hom.: 51305 Cov.: 33 AF XY: 0.817 AC XY: 60760 AN XY: 74402

African (AFR) AF: 0.677 AC: 28076 AN: 41458

American (AMR) AF: 0.738 AC: 11284 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 2959 AN: 3472

East Asian (EAS) AF: 0.786 AC: 4059 AN: 5164

South Asian (SAS) AF: 0.891 AC: 4298 AN: 4822

European-Finnish (FIN) AF: 0.958 AC: 10171 AN: 10620

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.889 AC: 60467 AN: 68022

Other (OTH) AF: 0.820 AC: 1734 AN: 2114

Alfa AF: 0.850 Hom.: 71450

Bravo AF: 0.789

Asia WGS AF: 0.807 AC: 2808 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.72
PhyloP100		0.34
Mutation Taster		=300/0	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: rs3747134; hg19: chr22-26877981;