rs115281140

Variant names:

• chr10-70600468-C-T
• rs115281140
• NM_001083116.3:c.435G>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.435G>A​(p.Val145Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00713 in 1,614,214 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (55 hom.)
• Consequence: PRF1 NM_001083116.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.388
• 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=-0.73).
• BP6: Variant 10-70600468-C-T is Benign according to our data. Variant chr10-70600468-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1712/152326) while in subpopulation AFR AF = 0.0225 (937/41568). AF 95% confidence interval is 0.0213. There are 21 homozygotes in GnomAd4. There are 783 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,Unknown 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.435G>A	p.Val145Val	synonymous	Exon 2 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.435G>A	p.Val145Val	synonymous	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.435G>A	p.Val145Val	synonymous	Exon 2 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.435G>A	p.Val145Val	synonymous	Exon 2 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.435G>A	p.Val145Val	synonymous	Exon 1 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1706 AN: 152208 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00685

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00604 AC: 1518 AN: 251448 AF XY: 0.00541

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00618

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00670 AC: 9793 AN: 1461888 Hom.: 55 Cov.: 34 AF XY: 0.00655 AC XY: 4761 AN XY: 727246

African (AFR) AF: 0.0228 AC: 765 AN: 33480

American (AMR) AF: 0.00700 AC: 313 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: 0.00536 AC: 462 AN: 86256

European-Finnish (FIN) AF: 0.000786 AC: 42 AN: 53420

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00695 AC: 7733 AN: 1112008

Other (OTH) AF: 0.00725 AC: 438 AN: 60396

GnomAD4 genome AF: 0.0112 AC: 1712 AN: 152326 Hom.: 21 Cov.: 32 AF XY: 0.0105 AC XY: 783 AN XY: 74498

African (AFR) AF: 0.0225 AC: 937 AN: 41568

American (AMR) AF: 0.00863 AC: 132 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00685 AC: 466 AN: 68024

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00749 Hom.: 9

Bravo AF: 0.0127

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hemophagocytic lymphohistiocytosis 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Lymphoma, non-Hodgkin, familial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.95
DANN	Benign	0.50
PhyloP100		0.39
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: rs115281140; hg19: chr10-72360224;