rs119471024

Variant names:

• chr22-26472391-C-A
• rs119471024
• NM_022081.6:c.412G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_022081.6(HPS4):​c.412G>T​(p.Glu138*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HPS4 NM_022081.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.799
• Publications: 5 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-26472391-C-A is Pathogenic according to our data. Variant chr22-26472391-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4131.Status of the report is no_assertion_criteria_provided, 0 stars.

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.412G>T	p.Glu138*	stop_gained	Exon 6 of 14	NP_071364.4
	HPS4	NM_001349900.2		c.412G>T	p.Glu138*	stop_gained	Exon 6 of 15	NP_001336829.1	F1LLU8
	HPS4	NM_001349901.1		c.412G>T	p.Glu138*	stop_gained	Exon 6 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.412G>T	p.Glu138*	stop_gained	Exon 6 of 14	ENSP00000381213.2	Q9NQG7-1
	HPS4	ENST00000402105.7	TSL:1	c.397G>T	p.Glu133*	stop_gained	Exon 4 of 12	ENSP00000384185.3	Q9NQG7-3
	HPS4	ENST00000439453.5	TSL:1	n.412G>T		non_coding_transcript_exon	Exon 6 of 14	ENSP00000406764.1	F8WC53

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460028 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726468

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110334

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hermansky-Pudlak syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.086	N
PhyloP100		0.80
Vest4		0.45
GERP RS		2.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs119471024; hg19: chr22-26868357;