chr22-26470757-C-T

Variant names:

• chr22-26470757-C-T
• rs13054747
• NM_022081.6:c.558G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022081.6(HPS4):​c.558G>A​(p.Ser186Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,614,016 control chromosomes in the GnomAD database, including 1,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S186S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (105 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1296 hom.)
• Consequence: HPS4 NM_022081.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.59
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 22-26470757-C-T is Benign according to our data. Variant chr22-26470757-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0353 (5367/152222) while in subpopulation NFE AF = 0.0411 (2795/67998). AF 95% confidence interval is 0.0398. There are 105 homozygotes in GnomAd4. There are 2525 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 105 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.558G>A	p.Ser186Ser	synonymous	Exon 7 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.558G>A	p.Ser186Ser	synonymous	Exon 7 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.558G>A	p.Ser186Ser	synonymous	Exon 7 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.558G>A	p.Ser186Ser	synonymous	Exon 7 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.543G>A	p.Ser181Ser	synonymous	Exon 5 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*76G>A		non_coding_transcript_exon	Exon 7 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 5362 AN: 152104 Hom.: 104 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0325 AC: 8157 AN: 251304 AF XY: 0.0326

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0391 AC: 57218 AN: 1461794 Hom.: 1296 Cov.: 32 AF XY: 0.0385 AC XY: 28022 AN XY: 727206

African (AFR) AF: 0.0266 AC: 890 AN: 33478

American (AMR) AF: 0.0234 AC: 1048 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2741 AN: 26132

East Asian (EAS) AF: 0.000730 AC: 29 AN: 39700

South Asian (SAS) AF: 0.0216 AC: 1864 AN: 86254

European-Finnish (FIN) AF: 0.0241 AC: 1285 AN: 53406

Middle Eastern (MID) AF: 0.0238 AC: 137 AN: 5758

European-Non Finnish (NFE) AF: 0.0422 AC: 46885 AN: 1111960

Other (OTH) AF: 0.0387 AC: 2339 AN: 60386

GnomAD4 genome AF: 0.0353 AC: 5367 AN: 152222 Hom.: 105 Cov.: 33 AF XY: 0.0339 AC XY: 2525 AN XY: 74438

African (AFR) AF: 0.0280 AC: 1163 AN: 41536

American (AMR) AF: 0.0382 AC: 584 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3468

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4822

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2795 AN: 67998

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0367 Hom.: 157

Bravo AF: 0.0358

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.3
DANN	Benign	0.85
PhyloP100		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13054747; hg19: chr22-26866723; COSMIC: COSV61103177; COSMIC: COSV61103177;