NM_001083116.3:c.539+82C>T

Variant names:

• chr10-70600282-G-A
• rs10999426
• NM_001083116.3:c.539+82C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.266
• Publications: 14 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.539+82C>T		intron_variant	Intron 2 of 2	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.539+82C>T		intron_variant	Intron 2 of 2		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.539+82C>T		intron_variant	Intron 2 of 2	5	NM_001083116.3	ENSP00000398568.1

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

African (AFR) AF: 0.0738 AC: 2389 AN: 32380

American (AMR) AF: 0.184 AC: 7327 AN: 39832

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 7901 AN: 25412

East Asian (EAS) AF: 0.0205 AC: 771 AN: 37650

South Asian (SAS) AF: 0.196 AC: 16069 AN: 82098

European-Finnish (FIN) AF: 0.252 AC: 11342 AN: 44972

Middle Eastern (MID) AF: 0.304 AC: 1605 AN: 5276

European-Non Finnish (NFE) AF: 0.322 AC: 352794 AN: 1094362

Other (OTH) AF: 0.271 AC: 16003 AN: 58988

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

African (AFR) AF: 0.0761 AC: 3158 AN: 41512

American (AMR) AF: 0.221 AC: 3377 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1091 AN: 3468

East Asian (EAS) AF: 0.0239 AC: 124 AN: 5182

South Asian (SAS) AF: 0.183 AC: 883 AN: 4822

European-Finnish (FIN) AF: 0.237 AC: 2499 AN: 10566

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21947 AN: 67928

Other (OTH) AF: 0.255 AC: 538 AN: 2106

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.60
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs10999426; hg19: chr10-72360038;