rs368524364

Variant names:

• chr10-70599089-G-A
• rs368524364
• NM_001083116.3:c.632C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001083116.3(PRF1):​c.632C>T​(p.Ala211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,008 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A211T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.267
• Publications: 8 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.

• 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 familial hemophagocytic lymphohistiocytosis 2, lymphoma, non-Hodgkin, familial, hereditary hemophagocytic lymphohistiocytosis, fatal post-viral neurodegenerative disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016103953).
• BP6: Variant 10-70599089-G-A is Benign according to our data. Variant chr10-70599089-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468308.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000591 (90/152364) while in subpopulation SAS AF = 0.017 (82/4828). AF 95% confidence interval is 0.014. There are 1 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR,Unknown gene

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.632C>T	p.Ala211Val	missense	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.632C>T	p.Ala211Val	missense	Exon 3 of 3	NP_005032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.632C>T	p.Ala211Val	missense	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.632C>T	p.Ala211Val	missense	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.632C>T	p.Ala211Val	missense	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00213 AC: 530 AN: 248812 AF XY: 0.00287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00108 AC: 1573 AN: 1461644 Hom.: 19 Cov.: 35 AF XY: 0.00154 AC XY: 1118 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0161 AC: 1388 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111896

Other (OTH) AF: 0.00118 AC: 71 AN: 60384

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.000899 AC XY: 67 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000967 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00238 AC: 289

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Familial hemophagocytic lymphohistiocytosis 2 (4)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Lymphoma, non-Hodgkin, familial (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.40	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.27
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.59
Sift	Benign	0.27	T
Sift4G	Uncertain	0.058	T
Polyphen		0.25	B
Vest4		0.64
MVP		0.68
MPC		0.12
ClinPred		0.028	T
GERP RS		0.21
Varity_R		0.057
gMVP		0.43
Mutation Taster		=98/2	polymorphism

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: rs368524364; hg19: chr10-72358845;