rs35418374

Variant names:

• chr10-70600892-C-A
• rs35418374
• NM_001083116.3:c.11G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70600892-C-A
• chr10-70600892-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001083116.3(PRF1):​c.11G>T​(p.Arg4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.016731 (below the threshold of 3.09). Trascript score misZ: 0.68523 (below the threshold of 3.09). GenCC associations: The gene is linked to lymphoma, non-Hodgkin, familial, hereditary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.123137504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRF1	NM_001083116.3	c.11G>T	p.Arg4Leu	missense_variant	Exon 2 of 3	ENST00000441259.2	NP_001076585.1
PRF1	NM_005041.6	c.11G>T	p.Arg4Leu	missense_variant	Exon 2 of 3		NP_005032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRF1	ENST00000441259.2	c.11G>T	p.Arg4Leu	missense_variant	Exon 2 of 3	5	NM_001083116.3	ENSP00000398568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437966 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 713116

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 39786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 38998

South Asian (SAS) AF: 0.00 AC: 0 AN: 83214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101618

Other (OTH) AF: 0.0000168 AC: 1 AN: 59628

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.24
DANN	Benign	0.81
DEOGEN2	Benign	0.18	.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.40	T;.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	.;L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.2	.;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	.;D;D
Sift4G	Benign	0.69	.;T;T
Polyphen		0.0	.;B;B
Vest4		0.082, 0.074
MutPred		0.27		Loss of methylation at R4 (P = 0.0312);Loss of methylation at R4 (P = 0.0312);Loss of methylation at R4 (P = 0.0312);
MVP		0.51
MPC		0.22
ClinPred		0.42	T
GERP RS		-6.2
Varity_R		0.054
gMVP		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35418374; hg19: chr10-72360648;