10-70598629-CAG-C

Variant names:

• chr10-70598629-CAG-C
• rs771552960
• NM_001083116.3:c.1090_1091delCT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001083116.3(PRF1):​c.1090_1091delCT​(p.Leu364GlufsTer93) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,460,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L364L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PRF1 NM_001083116.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.38
• Publications: 22 publications found

Genes affected

PRF1 (HGNC:9360): (perforin 1) This gene encodes a protein with structural similarities to complement component C9 that is important in immunity. This protein forms membrane pores that allow the release of granzymes and subsequent cytolysis of target cells. Whether pore formation occurs in the plasma membrane of target cells or in an endosomal membrane inside target cells is subject to debate. Mutations in this gene are associated with a variety of human disease including diabetes, multiple sclerosis, lymphomas, autoimmune lymphoproliferative syndrome (ALPS), aplastic anemia, and familial hemophagocytic lymphohistiocytosis type 2 (FHL2), a rare and lethal autosomal recessive disorder of early childhood. [provided by RefSeq, Aug 2017]

PALD1 (HGNC:23530): (phosphatase domain containing paladin 1) Predicted to enable protein tyrosine phosphatase activity. Predicted to be involved in peptidyl-tyrosine dephosphorylation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PP5: Variant 10-70598629-CAG-C is Pathogenic according to our data. Variant chr10-70598629-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 13721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.1090_1091delCT	p.Leu364GlufsTer93	frameshift_variant	Exon 3 of 3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.1090_1091delCT	p.Leu364GlufsTer93	frameshift_variant	Exon 3 of 3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.1090_1091delCT	p.Leu364GlufsTer93	frameshift_variant	Exon 3 of 3	5	NM_001083116.3	ENSP00000398568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247068 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460836 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 726790

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Pathogenic:2 Other:1

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu364Glufs*93) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 192 amino acid(s) of the PRF1 protein. This variant is present in population databases (rs771552960, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 11841437, 20015888, 23180437, 24578718, 26199792, 27896523, 29357941). ClinVar contains an entry for this variant (Variation ID: 13721). This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Arg390*) have been determined to be pathogenic (PMID: 17601962, 21152410, 29357941). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Seen only in persons of Japanese descent [Trizzino et al 2008] -

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aplastic anemia Pathogenic:1

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Familial hemophagocytic lymphohistiocytosis Pathogenic:1

Jul 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRF1 c.1090_1091delCT (p.Leu364GlufsX93) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 1.2e-05 in 247068 control chromosomes. c.1090_1091delCT has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (examples: Hoshini_2020, Hori_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32914282, 27896523). ClinVar contains an entry for this variant (Variation ID: 13721). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial Pathogenic:1

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=12/188	disease causing (ClinVar)

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: rs771552960; hg19: chr10-72358385;