rs739289

Variant names:

• chr22-26466187-C-A
• rs739289
• NM_022081.6:c.706+39G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-26466187-C-A
• chr22-26466187-C-G
• chr22-26466187-C-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+39G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,613,106 control chromosomes in the GnomAD database, including 616,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51970 hom., cov: 32)
  • Exomes 𝑓: 0.88 (564084 hom.)
• Consequence: HPS4 NM_022081.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.09
• Publications: 18 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-26466187-C-A is Benign according to our data. Variant chr22-26466187-C-A is described in ClinVar as Benign. ClinVar VariationId is 261537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 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.706+39G>T		intron	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.706+39G>T		intron	N/A	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.706+39G>T		intron	N/A	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.706+39G>T		intron	N/A	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.691+39G>T		intron	N/A	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*224+39G>T		intron	N/A	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124842 AN: 152054 Hom.: 51963 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.834

GnomAD2 exomes AF: 0.844 AC: 212227 AN: 251384 AF XY: 0.857

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.661

Gnomad ASJ exome AF: 0.867

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.892

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.877 AC: 1280845 AN: 1460934 Hom.: 564084 Cov.: 37 AF XY: 0.880 AC XY: 639402 AN XY: 726830

African (AFR) AF: 0.680 AC: 22758 AN: 33446

American (AMR) AF: 0.676 AC: 30197 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 22542 AN: 26130

East Asian (EAS) AF: 0.768 AC: 30482 AN: 39682

South Asian (SAS) AF: 0.905 AC: 78072 AN: 86240

European-Finnish (FIN) AF: 0.950 AC: 50745 AN: 53418

Middle Eastern (MID) AF: 0.891 AC: 5133 AN: 5762

European-Non Finnish (NFE) AF: 0.890 AC: 988482 AN: 1111190

Other (OTH) AF: 0.869 AC: 52434 AN: 60364

GnomAD4 genome AF: 0.821 AC: 124898 AN: 152172 Hom.: 51970 Cov.: 32 AF XY: 0.822 AC XY: 61187 AN XY: 74412

African (AFR) AF: 0.686 AC: 28451 AN: 41448

American (AMR) AF: 0.744 AC: 11376 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3005 AN: 3472

East Asian (EAS) AF: 0.786 AC: 4072 AN: 5182

South Asian (SAS) AF: 0.892 AC: 4300 AN: 4820

European-Finnish (FIN) AF: 0.958 AC: 10170 AN: 10618

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.893 AC: 60751 AN: 68016

Other (OTH) AF: 0.831 AC: 1756 AN: 2114

Alfa AF: 0.858 Hom.: 70813

Bravo AF: 0.796

Asia WGS AF: 0.809 AC: 2815 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hermansky-Pudlak syndrome 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.027
DANN	Benign	0.62
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs739289; hg19: chr22-26862153; COSMIC: COSV61102900; COSMIC: COSV61102900;