10-70597914-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001083116.3(PRF1):c.*139C>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 0.00808 in 1,073,472 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (49 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 10-70597914-G-A is Benign according to our data. Variant chr10-70597914-G-A is described in ClinVar as [Benign]. Clinvar id is 879865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2130/152068) while in subpopulation AFR AF= 0.0322 (1335/41448). AF 95% confidence interval is 0.0308. There are 27 homozygotes in gnomad4. There are 974 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.*139C>T		3_prime_UTR_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.*139C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.*139C>T		3_prime_UTR_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2123 AN: 151954 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00688

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00711 AC: 6548 AN: 921404 Hom.: 49 Cov.: 13 AF XY: 0.00697 AC XY: 3265 AN XY: 468556

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.00779

Gnomad4 ASJ exome AF: 0.000140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00524

Gnomad4 FIN exome AF: 0.000938

Gnomad4 NFE exome AF: 0.00724

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.0140 AC: 2130 AN: 152068 Hom.: 27 Cov.: 33 AF XY: 0.0131 AC XY: 974 AN XY: 74332

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.00688

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.000566 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.32
Dann	Benign	0.73

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: rs56743633; hg19: chr10-72357670;