rs2228018

Variant names:

• chr10-70600807-C-T
• rs2228018
• NM_001083116.3:c.96G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083116.3(PRF1):​c.96G>A​(p.Lys32Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,612,242 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (9 hom.)
• Consequence: PRF1 NM_001083116.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.250
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-70600807-C-T is Benign according to our data. Variant chr10-70600807-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00407 (620/152376) while in subpopulation AFR AF = 0.0142 (589/41588). AF 95% confidence interval is 0.0132. There are 8 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	NM_001083116.3	MANE Select	c.96G>A	p.Lys32Lys	synonymous	Exon 2 of 3	NP_001076585.1
	PRF1	NM_005041.6		c.96G>A	p.Lys32Lys	synonymous	Exon 2 of 3	NP_005032.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.96G>A	p.Lys32Lys	synonymous	Exon 2 of 3	ENSP00000398568.1
	PRF1	ENST00000373209.2	TSL:1	c.96G>A	p.Lys32Lys	synonymous	Exon 2 of 3	ENSP00000362305.1
	PRF1	ENST00000638674.1	TSL:5	c.96G>A	p.Lys32Lys	synonymous	Exon 2 of 3	ENSP00000492048.1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152258 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00108 AC: 265 AN: 244932 AF XY: 0.000782

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000821

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000447 AC: 653 AN: 1459866 Hom.: 9 Cov.: 34 AF XY: 0.000410 AC XY: 298 AN XY: 726088

African (AFR) AF: 0.0151 AC: 506 AN: 33466

American (AMR) AF: 0.000762 AC: 34 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.000423 AC: 11 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5738

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1110978

Other (OTH) AF: 0.00119 AC: 72 AN: 60284

GnomAD4 genome AF: 0.00407 AC: 620 AN: 152376 Hom.: 8 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74518

African (AFR) AF: 0.0142 AC: 589 AN: 41588

American (AMR) AF: 0.00118 AC: 18 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00216 Hom.: 1

Bravo AF: 0.00466

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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)
-	-	1	Lymphoma, non-Hodgkin, familial (1)
-	-	1	not specified (1)
-	-	1	PRF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.2
DANN	Benign	0.79
PhyloP100		-0.25
Mutation Taster		=100/0	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: rs2228018; hg19: chr10-72360563;