rs713998

Variant names:

• chr22-26466246-T-C
• rs713998
• NM_022081.6:c.686A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-26466246-T-C
• chr22-26466246-T-A

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.686A>G​(p.Glu229Gly) 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 1,613,862 control chromosomes in the GnomAD database, including 616,234 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E229E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.82 (51959 hom., cov: 32)
  • Exomes 𝑓: 0.88 (564275 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.170
• Publications: 40 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=8.188877E-7).
• BP6: Variant 22-26466246-T-C is Benign according to our data. Variant chr22-26466246-T-C is described in ClinVar as Benign. ClinVar VariationId is 163674.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.686A>G	p.Glu229Gly	missense	Exon 9 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.686A>G	p.Glu229Gly	missense	Exon 9 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.686A>G	p.Glu229Gly	missense	Exon 9 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.686A>G	p.Glu229Gly	missense	Exon 9 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.671A>G	p.Glu224Gly	missense	Exon 7 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*204A>G		non_coding_transcript_exon	Exon 9 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124833 AN: 152074 Hom.: 51952 Cov.: 32

Gnomad AFR AF: 0.686

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: 0.833

GnomAD2 exomes AF: 0.844 AC: 212237 AN: 251394 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: 1281410 AN: 1461670 Hom.: 564275 Cov.: 52 AF XY: 0.880 AC XY: 639631 AN XY: 727146

African (AFR) AF: 0.681 AC: 22784 AN: 33472

American (AMR) AF: 0.676 AC: 30208 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 22544 AN: 26130

East Asian (EAS) AF: 0.768 AC: 30492 AN: 39698

South Asian (SAS) AF: 0.905 AC: 78082 AN: 86250

European-Finnish (FIN) AF: 0.950 AC: 50741 AN: 53414

Middle Eastern (MID) AF: 0.891 AC: 5138 AN: 5768

European-Non Finnish (NFE) AF: 0.889 AC: 988972 AN: 1111840

Other (OTH) AF: 0.869 AC: 52449 AN: 60388

GnomAD4 genome AF: 0.821 AC: 124889 AN: 152192 Hom.: 51959 Cov.: 32 AF XY: 0.822 AC XY: 61178 AN XY: 74418

African (AFR) AF: 0.686 AC: 28458 AN: 41482

American (AMR) AF: 0.743 AC: 11370 AN: 15294

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

East Asian (EAS) AF: 0.786 AC: 4068 AN: 5176

South Asian (SAS) AF: 0.892 AC: 4307 AN: 4828

European-Finnish (FIN) AF: 0.958 AC: 10164 AN: 10612

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

European-Non Finnish (NFE) AF: 0.893 AC: 60746 AN: 68010

Other (OTH) AF: 0.830 AC: 1754 AN: 2112

Alfa AF: 0.864 Hom.: 190019

Bravo AF: 0.796

TwinsUK AF: 0.883 AC: 3276

ALSPAC AF: 0.882 AC: 3400

ESP6500AA AF: 0.689 AC: 3034

ESP6500EA AF: 0.888 AC: 7638

ExAC AF: 0.849 AC: 103023

Asia WGS AF: 0.809 AC: 2814 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
-	-	4	not specified (4)
-	-	3	not provided (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	0.042
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.62
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.17
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.65	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.049
ClinPred		0.0022	T
GERP RS		0.46
Varity_R		0.023
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs713998; hg19: chr22-26862212; COSMIC: COSV61102904; COSMIC: COSV61102904;