10-70600892-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001083116.3(PRF1):​c.11G>A​(p.Arg4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,590,208 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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: 𝑓 0.024 (162 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (111 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: -1.04
• Publications: 11 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 -19 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 lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006365478).
• BP6: Variant 10-70600892-C-T is Benign according to our data. Variant chr10-70600892-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 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.11G>A	p.Arg4His	missense	Exon 2 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.11G>A	p.Arg4His	missense	Exon 2 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.11G>A	p.Arg4His	missense	Exon 2 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.11G>A	p.Arg4His	missense	Exon 2 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.11G>A	p.Arg4His	missense	Exon 1 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3620 AN: 152126 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00594 AC: 1175 AN: 197740 AF XY: 0.00456

Gnomad AFR exome AF: 0.0850

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00239 AC: 3439 AN: 1437964 Hom.: 111 Cov.: 34 AF XY: 0.00204 AC XY: 1457 AN XY: 713116

African (AFR) AF: 0.0820 AC: 2730 AN: 33312

American (AMR) AF: 0.00508 AC: 202 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: 0.000240 AC: 20 AN: 83214

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

Middle Eastern (MID) AF: 0.00424 AC: 22 AN: 5188

European-Non Finnish (NFE) AF: 0.000120 AC: 132 AN: 1101618

Other (OTH) AF: 0.00558 AC: 333 AN: 59628

GnomAD4 genome AF: 0.0238 AC: 3628 AN: 152244 Hom.: 162 Cov.: 32 AF XY: 0.0231 AC XY: 1718 AN XY: 74446

African (AFR) AF: 0.0831 AC: 3451 AN: 41532

American (AMR) AF: 0.00850 AC: 130 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68006

Other (OTH) AF: 0.0147 AC: 31 AN: 2108

Alfa AF: 0.00892 Hom.: 92

Bravo AF: 0.0268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0786 AC: 344

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00685 AC: 825

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hemophagocytic lymphohistiocytosis 2 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
1	-	-	Aplastic anemia (1)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.065	N
PhyloP100		-1.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.043
MVP		0.63
MPC		0.34
ClinPred		0.026	T
GERP RS		-6.2
Varity_R		0.035
gMVP		0.31
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: rs35418374; hg19: chr10-72360648; COSMIC: COSV64614479;