NM_022081.6:c.*1962C>T

Variant names:

• chr22-26451271-G-A
• rs5761533
• NM_022081.6:c.*1962C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022081.6(HPS4):​c.*1962C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,046 control chromosomes in the GnomAD database, including 15,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15638 hom., cov: 32)
• Consequence: HPS4 NM_022081.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.734
• Publications: 6 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307305 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-26451271-G-A is Benign according to our data. Variant chr22-26451271-G-A is described in ClinVar as Benign. ClinVar VariationId is 903363.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022081.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	NM_022081.6	MANE Select	c.*1962C>T		3_prime_UTR	Exon 14 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.*1962C>T		3_prime_UTR	Exon 15 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.*1962C>T		3_prime_UTR	Exon 15 of 15	NP_001336830.1	F1LLU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPS4	ENST00000398145.7	TSL:1 MANE Select	c.*1962C>T		3_prime_UTR	Exon 14 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000491142.2	TSL:2	n.*1035C>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000514221.1	Q9NQG7-1
	ENSG00000307305	ENST00000824999.1		n.735G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67905 AN: 151928 Hom.: 15641 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.477

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67909 AN: 152046 Hom.: 15638 Cov.: 32 AF XY: 0.451 AC XY: 33525 AN XY: 74328

African (AFR) AF: 0.343 AC: 14201 AN: 41450

American (AMR) AF: 0.462 AC: 7051 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1934 AN: 3472

East Asian (EAS) AF: 0.486 AC: 2514 AN: 5172

South Asian (SAS) AF: 0.387 AC: 1863 AN: 4820

European-Finnish (FIN) AF: 0.588 AC: 6213 AN: 10566

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32587 AN: 67976

Other (OTH) AF: 0.470 AC: 991 AN: 2110

Alfa AF: 0.459 Hom.: 2101

Bravo AF: 0.431

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hermansky-Pudlak syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.51
DANN	Benign	0.65
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5761533; hg19: chr22-26847237;