10-70597879-A-G

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.*174T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 747,346 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (11 hom., cov: 32)
  • Exomes 𝑓: 0.010 (62 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.636

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=-0.9).
• BP6: Variant 10-70597879-A-G is Benign according to our data. Variant chr10-70597879-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 879864.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-70597879-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00918 (1396/152024) while in subpopulation NFE AF= 0.0142 (968/67964). AF 95% confidence interval is 0.0135. There are 11 homozygotes in gnomad4. There are 679 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.*174T>C		3_prime_UTR_variant	3/3	ENST00000441259.2
PRF1	NM_005041.6	c.*174T>C		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.*174T>C		3_prime_UTR_variant	3/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1397 AN: 151906 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.0104 AC: 6211 AN: 595322 Hom.: 62 Cov.: 8 AF XY: 0.0102 AC XY: 3172 AN XY: 311636

Gnomad4 AFR exome AF: 0.00264

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.000709

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.00839

GnomAD4 genome AF: 0.00918 AC: 1396 AN: 152024 Hom.: 11 Cov.: 32 AF XY: 0.00914 AC XY: 679 AN XY: 74312

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0120 Hom.: 0

Bravo AF: 0.00769

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.0
Dann	Benign	0.39

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: rs74513535; hg19: chr10-72357635;