rs201909472

chr10-70600791-C-Achr10-70600791-C-Gchr10-70600791-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001083116.3(PRF1):c.112G>T(p.Val38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,386 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V38M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001083116.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.112G>T	p.Val38Leu	missense_variant	2/3	ENST00000441259.2
PRF1	NM_005041.6	c.112G>T	p.Val38Leu	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.112G>T	p.Val38Leu	missense_variant	2/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458386 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	17
Dann	Benign	0.95
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.61	T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Uncertain	0.57	T
Polyphen		0.43	.;B;B
Vest4		0.16, 0.14
MutPred		0.78		Gain of disorder (P = 0.1993);Gain of disorder (P = 0.1993);Gain of disorder (P = 0.1993);
MVP		0.82
MPC		0.19
ClinPred		0.23	T
GERP RS		2.8
Varity_R		0.098
gMVP		0.92

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: rs201909472; hg19: chr10-72360547;