rs10999426

Positions:

• chr10-70600282-G-A
• chr10-70600282-G-C

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.539+82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,573,042 control chromosomes in the GnomAD database, including 69,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4813 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64989 hom.)
• Consequence: PRF1 NM_001083116.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.266

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=-0.84).
• BP6: Variant 10-70600282-G-A is Benign according to our data. Variant chr10-70600282-G-A is described in ClinVar as [Benign]. Clinvar id is 1181354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.539+82C>T		intron_variant		ENST00000441259.2
PRF1	NM_005041.6	c.539+82C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.539+82C>T		intron_variant		5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34058 AN: 151954 Hom.: 4815 Cov.: 32

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.293 AC: 416201 AN: 1420970 Hom.: 64989 AF XY: 0.291 AC XY: 204962 AN XY: 704050

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.224 AC: 34055 AN: 152072 Hom.: 4813 Cov.: 32 AF XY: 0.219 AC XY: 16290 AN XY: 74336

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.0239

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.255

Alfa AF: 0.264 Hom.: 749

Bravo AF: 0.218

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.60

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: rs10999426; hg19: chr10-72360038;