rs116769827

Variant names:

• chr22-26464569-G-C
• rs116769827
• NM_022081.6:c.1061C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-26464569-G-C
• chr22-26464569-G-A
• chr22-26464569-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022081.6(HPS4):​c.1061C>G​(p.Ser354Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,220 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S354T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (19 hom.)
• Consequence: HPS4 NM_022081.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.416
• Publications: 1 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=0.0024479628).
• BP6: Variant 22-26464569-G-C is Benign according to our data. Variant chr22-26464569-G-C is described in ClinVar as Benign. ClinVar VariationId is 226656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00808 (1231/152338) while in subpopulation AFR AF = 0.0283 (1175/41570). AF 95% confidence interval is 0.0269. There are 13 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.1061C>G	p.Ser354Cys	missense	Exon 11 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.1115C>G	p.Ser372Cys	missense	Exon 12 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.1115C>G	p.Ser372Cys	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.1061C>G	p.Ser354Cys	missense	Exon 11 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.1046C>G	p.Ser349Cys	missense	Exon 9 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*579C>G		non_coding_transcript_exon	Exon 11 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152220 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00205 AC: 516 AN: 251476 AF XY: 0.00146

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000780 AC: 1140 AN: 1461882 Hom.: 19 Cov.: 34 AF XY: 0.000646 AC XY: 470 AN XY: 727246

African (AFR) AF: 0.0276 AC: 923 AN: 33478

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1112012

Other (OTH) AF: 0.00167 AC: 101 AN: 60396

GnomAD4 genome AF: 0.00808 AC: 1231 AN: 152338 Hom.: 13 Cov.: 33 AF XY: 0.00754 AC XY: 562 AN XY: 74504

African (AFR) AF: 0.0283 AC: 1175 AN: 41570

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000708 Hom.: 0

Bravo AF: 0.00890

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00264 AC: 321

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.22
DANN	Benign	0.55
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.074	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.42
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.018
Sift	Benign	0.80	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.092
MVP		0.22
MPC		0.043
ClinPred		0.0020	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.043
gMVP		0.18
Mutation Taster		=100/0	polymorphism

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: rs116769827; hg19: chr22-26860535;