10-70597957-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083116.3(PRF1):c.*96G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,519,626 control chromosomes in the GnomAD database, including 148,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21458 hom., cov: 32)
  • Exomes 𝑓: 0.43 (127383 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.754

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-70597957-C-T is Benign according to our data. Variant chr10-70597957-C-T is described in ClinVar as [Benign]. Clinvar id is 300324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.*96G>A		3_prime_UTR_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.*96G>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.*96G>A		3_prime_UTR_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77439 AN: 151856 Hom.: 21422 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.492

GnomAD4 exome AF: 0.425 AC: 581328 AN: 1367652 Hom.: 127383 Cov.: 24 AF XY: 0.427 AC XY: 291319 AN XY: 682110

Gnomad4 AFR exome AF: 0.740

Gnomad4 AMR exome AF: 0.528

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.516

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.447

GnomAD4 genome AF: 0.510 AC: 77540 AN: 151974 Hom.: 21458 Cov.: 32 AF XY: 0.509 AC XY: 37828 AN XY: 74274

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.513

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.492

Alfa AF: 0.471 Hom.: 5856

Bravo AF: 0.533

Asia WGS AF: 0.521 AC: 1815 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 14, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Familial hemophagocytic lymphohistiocytosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1889490; hg19: chr10-72357713; COSMIC: COSV64614709;