rs5752330

Variant names:

• chr22-26463976-C-T
• rs5752330
• NM_022081.6:c.1654G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-26463976-C-T
• chr22-26463976-C-A
• chr22-26463976-C-G

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.1654G>A​(p.Val552Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,614,046 control chromosomes in the GnomAD database, including 616,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V552V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.82 (51962 hom., cov: 34)
  • Exomes 𝑓: 0.88 (564237 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.611
• Publications: 42 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 (MetaRNN=1.4732882E-6).
• BP6: Variant 22-26463976-C-T is Benign according to our data. Variant chr22-26463976-C-T is described in ClinVar as Benign. ClinVar VariationId is 163672.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.1654G>A	p.Val552Met	missense	Exon 11 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.1708G>A	p.Val570Met	missense	Exon 12 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.1708G>A	p.Val570Met	missense	Exon 12 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.1654G>A	p.Val552Met	missense	Exon 11 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.1639G>A	p.Val547Met	missense	Exon 9 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*1172G>A		non_coding_transcript_exon	Exon 11 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124844 AN: 152114 Hom.: 51955 Cov.: 34

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.891

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: 212106 AN: 251272 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: 1281430 AN: 1461814 Hom.: 564237 Cov.: 68 AF XY: 0.880 AC XY: 639642 AN XY: 727208

African (AFR) AF: 0.680 AC: 22776 AN: 33480

American (AMR) AF: 0.675 AC: 30204 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 22547 AN: 26136

East Asian (EAS) AF: 0.768 AC: 30490 AN: 39696

South Asian (SAS) AF: 0.905 AC: 78085 AN: 86256

European-Finnish (FIN) AF: 0.950 AC: 50728 AN: 53400

Middle Eastern (MID) AF: 0.891 AC: 5137 AN: 5768

European-Non Finnish (NFE) AF: 0.889 AC: 989018 AN: 1111968

Other (OTH) AF: 0.868 AC: 52445 AN: 60394

GnomAD4 genome AF: 0.820 AC: 124900 AN: 152232 Hom.: 51962 Cov.: 34 AF XY: 0.822 AC XY: 61190 AN XY: 74446

African (AFR) AF: 0.686 AC: 28459 AN: 41502

American (AMR) AF: 0.743 AC: 11373 AN: 15300

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

East Asian (EAS) AF: 0.785 AC: 4049 AN: 5156

South Asian (SAS) AF: 0.892 AC: 4310 AN: 4834

European-Finnish (FIN) AF: 0.958 AC: 10177 AN: 10624

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

European-Non Finnish (NFE) AF: 0.893 AC: 60754 AN: 68028

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

Alfa AF: 0.862 Hom.: 215985

Bravo AF: 0.796

TwinsUK AF: 0.883 AC: 3276

ALSPAC AF: 0.883 AC: 3402

ESP6500AA AF: 0.688 AC: 3033

ESP6500EA AF: 0.888 AC: 7638

ExAC AF: 0.849 AC: 103013

Asia WGS AF: 0.809 AC: 2813 AN: 3478

EpiCase AF: 0.895

EpiControl AF: 0.888

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hermansky-Pudlak syndrome (1)
-	-	1	Hermansky-Pudlak syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.61
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.043
Sift	Benign	0.084	T
Sift4G	Uncertain	0.018	D
Polyphen		0.90	P
Vest4		0.072
MPC		0.17
ClinPred		0.021	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.58
Mutation Taster		=99/1	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: rs5752330; hg19: chr22-26859942; COSMIC: COSV61105153; COSMIC: COSV61105153;