rs35993959

Variant names:

• chr22-26457915-G-A
• rs35993959
• NM_022081.6:c.1899C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022081.6(HPS4):​c.1899C>T​(p.Val633Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,614,188 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: HPS4 NM_022081.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.628
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 22-26457915-G-A is Benign according to our data. Variant chr22-26457915-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.628 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2177/152362) while in subpopulation AFR AF = 0.0493 (2051/41580). AF 95% confidence interval is 0.0475. There are 53 homozygotes in GnomAd4. There are 957 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 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.1899C>T	p.Val633Val	synonymous	Exon 13 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.1953C>T	p.Val651Val	synonymous	Exon 14 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.1953C>T	p.Val651Val	synonymous	Exon 14 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.1899C>T	p.Val633Val	synonymous	Exon 13 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.1884C>T	p.Val628Val	synonymous	Exon 11 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.*1417C>T		non_coding_transcript_exon	Exon 13 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2177 AN: 152244 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00382 AC: 959 AN: 251230 AF XY: 0.00283

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00144 AC: 2104 AN: 1461826 Hom.: 39 Cov.: 30 AF XY: 0.00125 AC XY: 909 AN XY: 727216

African (AFR) AF: 0.0504 AC: 1689 AN: 33480

American (AMR) AF: 0.00286 AC: 128 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: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112008

Other (OTH) AF: 0.00343 AC: 207 AN: 60394

GnomAD4 genome AF: 0.0143 AC: 2177 AN: 152362 Hom.: 53 Cov.: 31 AF XY: 0.0128 AC XY: 957 AN XY: 74504

African (AFR) AF: 0.0493 AC: 2051 AN: 41580

American (AMR) AF: 0.00666 AC: 102 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68042

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00679 Hom.: 22

Bravo AF: 0.0169

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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	-0.38
CADD	Benign	9.5
DANN	Benign	0.79
PhyloP100		0.63
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: rs35993959; hg19: chr22-26853881;