rs3758562

Variant names:

• chr10-70602324-G-A
• rs3758562
• NM_001083116.3:c.-31+321C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001083116.3(PRF1):​c.-31+321C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 152,036 control chromosomes in the GnomAD database, including 35,868 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (35868 hom., cov: 32)
• Consequence: PRF1 NM_001083116.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083116.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	NM_001083116.3	MANE Select	c.-31+321C>T		intron	N/A	NP_001076585.1
	PRF1	NM_005041.6		c.-5+321C>T		intron	N/A	NP_005032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.-31+321C>T		intron	N/A	ENSP00000398568.1
	PRF1	ENST00000373209.2	TSL:1	c.-5+321C>T		intron	N/A	ENSP00000362305.1
	PRF1	ENST00000862973.1		c.-1422C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104211 AN: 151918 Hom.: 35842 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.686 AC: 104293 AN: 152036 Hom.: 35868 Cov.: 32 AF XY: 0.689 AC XY: 51204 AN XY: 74334

African (AFR) AF: 0.676 AC: 28035 AN: 41448

American (AMR) AF: 0.689 AC: 10520 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2358 AN: 3468

East Asian (EAS) AF: 0.746 AC: 3862 AN: 5178

South Asian (SAS) AF: 0.732 AC: 3532 AN: 4822

European-Finnish (FIN) AF: 0.748 AC: 7916 AN: 10580

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45898 AN: 67958

Other (OTH) AF: 0.670 AC: 1413 AN: 2110

Alfa AF: 0.673 Hom.: 57903

Bravo AF: 0.676

Asia WGS AF: 0.736 AC: 2561 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.51
PhyloP100		-0.33
PromoterAI		0.015	Neutral
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: rs3758562; hg19: chr10-72362080;