rs145463632

Variant names:

• chr10-70598721-C-T
• rs145463632
• NM_001083116.3:c.1000G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-70598721-C-T
• chr10-70598721-C-A
• chr10-70598721-C-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BP4_Strong

The NM_001083116.3(PRF1):​c.1000G>A​(p.Gly334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. G334D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: PRF1 NM_001083116.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: -0.832
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083116.3
• 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=0.007969499).

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.1000G>A	p.Gly334Ser	missense	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.1000G>A	p.Gly334Ser	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.1000G>A	p.Gly334Ser	missense	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.1000G>A	p.Gly334Ser	missense	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.1000G>A	p.Gly334Ser	missense	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000450 AC: 113 AN: 251062 AF XY: 0.000413

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000386 AC: 565 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.000388 AC XY: 282 AN XY: 727226

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000360 AC: 400 AN: 1112008

Other (OTH) AF: 0.000431 AC: 26 AN: 60392

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74362

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000497 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Familial hemophagocytic lymphohistiocytosis 2 (3)
-	2	-	not provided (2)
-	1	-	Aplastic anemia;C1863727:Familial hemophagocytic lymphohistiocytosis 2;C4721532:Lymphoma, non-Hodgkin, familial (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.55
DANN	Benign	0.56
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.7	N
PhyloP100		-0.83
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.2	N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.073
MVP		0.33
MPC		0.11
ClinPred		0.0063	T
GERP RS		-1.1
Varity_R		0.039
gMVP		0.26
Mutation Taster		=30/70	disease causing

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: rs145463632; hg19: chr10-72358477;