10-70597964-G-A

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.*89C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,537,796 control chromosomes in the GnomAD database, including 5,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (966 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4453 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.346

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=-0.91).
• BP6: Variant 10-70597964-G-A is Benign according to our data. Variant chr10-70597964-G-A is described in ClinVar as [Benign]. Clinvar id is 300325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.*89C>T		3_prime_UTR_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.*89C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.*89C>T		3_prime_UTR_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.0983 AC: 14943 AN: 152022 Hom.: 966 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0886

GnomAD4 exome AF: 0.0752 AC: 104167 AN: 1385656 Hom.: 4453 Cov.: 29 AF XY: 0.0749 AC XY: 51774 AN XY: 691182

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0441

Gnomad4 ASJ exome AF: 0.0744

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.0687

Gnomad4 FIN exome AF: 0.0389

Gnomad4 NFE exome AF: 0.0772

Gnomad4 OTH exome AF: 0.0763

GnomAD4 genome AF: 0.0983 AC: 14951 AN: 152140 Hom.: 966 Cov.: 32 AF XY: 0.0954 AC XY: 7098 AN XY: 74386

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0583

Gnomad4 ASJ AF: 0.0776

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.0691

Gnomad4 FIN AF: 0.0361

Gnomad4 NFE AF: 0.0795

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.0667 Hom.: 194

Bravo AF: 0.103

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-0.91
Cadd	Benign	1.1
Dann	Benign	0.61

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: rs6480459; hg19: chr10-72357720;