NM_001083116.3:c.539+61G>A

Variant names:

• chr10-70600303-C-T
• rs10999427
• NM_001083116.3:c.539+61G>A

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+61G>A 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 1,601,052 control chromosomes in the GnomAD database, including 70,918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4810 hom., cov: 32)
  • Exomes 𝑓: 0.29 (66108 hom.)
• Consequence: PRF1 NM_001083116.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.130
• Publications: 8 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 10-70600303-C-T is Benign according to our data. Variant chr10-70600303-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.539+61G>A		intron_variant	Intron 2 of 2	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.539+61G>A		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+61G>A		intron_variant	Intron 2 of 2	5	NM_001083116.3	ENSP00000398568.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34054 AN: 151918 Hom.: 4812 Cov.: 32

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.292 AC: 423774 AN: 1449016 Hom.: 66108 AF XY: 0.291 AC XY: 209479 AN XY: 720064

African (AFR) AF: 0.0738 AC: 2442 AN: 33106

American (AMR) AF: 0.182 AC: 7897 AN: 43414

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8063 AN: 25916

East Asian (EAS) AF: 0.0206 AC: 805 AN: 39100

South Asian (SAS) AF: 0.196 AC: 16628 AN: 84836

European-Finnish (FIN) AF: 0.251 AC: 12472 AN: 49776

Middle Eastern (MID) AF: 0.305 AC: 1724 AN: 5652

European-Non Finnish (NFE) AF: 0.323 AC: 357422 AN: 1107230

Other (OTH) AF: 0.272 AC: 16321 AN: 59986

GnomAD4 genome AF: 0.224 AC: 34051 AN: 152036 Hom.: 4810 Cov.: 32 AF XY: 0.219 AC XY: 16289 AN XY: 74324

African (AFR) AF: 0.0762 AC: 3163 AN: 41516

American (AMR) AF: 0.221 AC: 3379 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1093 AN: 3470

East Asian (EAS) AF: 0.0236 AC: 122 AN: 5176

South Asian (SAS) AF: 0.183 AC: 882 AN: 4818

European-Finnish (FIN) AF: 0.236 AC: 2495 AN: 10550

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21940 AN: 67910

Other (OTH) AF: 0.256 AC: 539 AN: 2104

Alfa AF: 0.186 Hom.: 738

Bravo AF: 0.218

Asia WGS AF: 0.107 AC: 371 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 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 35. 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	0.75
PhyloP100		0.13
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: rs10999427; hg19: chr10-72360059;