chr10-70598966-T-C

Variant names:

• chr10-70598966-T-C
• rs28933375
• NM_001083116.3:c.755A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_005041.6(PRF1):​c.755A>G​(p.Asn252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,614,236 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N252N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (42 hom.)
• Consequence: PRF1 NM_005041.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 0.935
• Publications: 41 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 -10 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_005041.6
• 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=0.0023942888).
• BP6: Variant 10-70598966-T-C is Benign according to our data. Variant chr10-70598966-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13716.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00746 (1136/152350) while in subpopulation AFR AF = 0.00928 (386/41590). AF 95% confidence interval is 0.00852. There are 18 homozygotes in GnomAd4. There are 519 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005041.6. 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.755A>G	p.Asn252Ser	missense	Exon 3 of 3	NP_001076585.1
	PRF1	NM_005041.6		c.755A>G	p.Asn252Ser	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.755A>G	p.Asn252Ser	missense	Exon 3 of 3	ENSP00000398568.1
	PRF1	ENST00000373209.2	TSL:1	c.755A>G	p.Asn252Ser	missense	Exon 3 of 3	ENSP00000362305.1
	PRF1	ENST00000862973.1		c.755A>G	p.Asn252Ser	missense	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1130 AN: 152232 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00921

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00682

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00503 AC: 1264 AN: 251430 AF XY: 0.00466

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00631 AC: 9221 AN: 1461886 Hom.: 42 Cov.: 35 AF XY: 0.00619 AC XY: 4501 AN XY: 727246

African (AFR) AF: 0.0100 AC: 336 AN: 33480

American (AMR) AF: 0.00617 AC: 276 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00531 AC: 458 AN: 86258

European-Finnish (FIN) AF: 0.000768 AC: 41 AN: 53414

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00692 AC: 7700 AN: 1112010

Other (OTH) AF: 0.00621 AC: 375 AN: 60396

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152350 Hom.: 18 Cov.: 32 AF XY: 0.00697 AC XY: 519 AN XY: 74506

African (AFR) AF: 0.00928 AC: 386 AN: 41590

American (AMR) AF: 0.00758 AC: 116 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00682 AC: 464 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00635 Hom.: 14

Bravo AF: 0.00831

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00517 AC: 628

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00557

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	5	not specified (5)
-	1	2	Familial hemophagocytic lymphohistiocytosis 2 (3)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.2
DANN	Benign	0.58
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.94
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.041
MVP		0.71
MPC		0.087
ClinPred		0.0042	T
GERP RS		4.7
Varity_R		0.064
gMVP		0.52
Mutation Taster		=92/8	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: rs28933375; hg19: chr10-72358722; COSMIC: COSV64615354;