rs12161733

Variant names:

• chr10-70600893-G-A
• rs12161733
• NM_001083116.3:c.10C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70600893-G-A
• chr10-70600893-G-C

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.10C>T​(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,587,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R4H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.03
• Publications: 10 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 lymphoma, non-Hodgkin, familial, familial hemophagocytic lymphohistiocytosis 2, fatal post-viral neurodegenerative disorder, hereditary hemophagocytic lymphohistiocytosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0055696666).
• BP6: Variant 10-70600893-G-A is Benign according to our data. Variant chr10-70600893-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536220.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00168 (256/152308) while in subpopulation EAS AF = 0.00637 (33/5180). AF 95% confidence interval is 0.00466. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 Unknown,AR 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.10C>T	p.Arg4Cys	missense	Exon 2 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.10C>T	p.Arg4Cys	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.10C>T	p.Arg4Cys	missense	Exon 2 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.10C>T	p.Arg4Cys	missense	Exon 2 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.10C>T	p.Arg4Cys	missense	Exon 1 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000913 AC: 176 AN: 192828 AF XY: 0.000879

Gnomad AFR exome AF: 0.00559

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00690

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.000199

GnomAD4 exome AF: 0.000265 AC: 381 AN: 1435474 Hom.: 4 Cov.: 34 AF XY: 0.000264 AC XY: 188 AN XY: 711604

African (AFR) AF: 0.00526 AC: 175 AN: 33268

American (AMR) AF: 0.000356 AC: 14 AN: 39330

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25564

East Asian (EAS) AF: 0.00324 AC: 126 AN: 38910

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50406

Middle Eastern (MID) AF: 0.000194 AC: 1 AN: 5142

European-Non Finnish (NFE) AF: 0.0000309 AC: 34 AN: 1100358

Other (OTH) AF: 0.000470 AC: 28 AN: 59538

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74472

African (AFR) AF: 0.00503 AC: 209 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15302

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

East Asian (EAS) AF: 0.00637 AC: 33 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000709 Hom.: 0

Bravo AF: 0.00177

ESP6500AA AF: 0.00275 AC: 12

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000806 AC: 97

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial (1)
-	-	1	Familial hemophagocytic lymphohistiocytosis 2 (1)
-	-	1	not specified (1)
-	-	1	PRF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L
PhyloP100		-2.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.086
MVP		0.44
MPC		0.44
ClinPred		0.022	T
GERP RS		-7.1
Varity_R		0.10
gMVP		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12161733; hg19: chr10-72360649;