rs885821

Variant names:

• chr10-70598899-G-A
• rs885821
• NM_001083116.3:c.822C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70598899-G-A
• chr10-70598899-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083116.3(PRF1):​c.822C>T​(p.Ala274Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,614,136 control chromosomes in the GnomAD database, including 26,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2187 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24634 hom.)
• Consequence: PRF1 NM_001083116.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -3.43
• Publications: 32 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=-0.85).
• BP6: Variant 10-70598899-G-A is Benign according to our data. Variant chr10-70598899-G-A is described in ClinVar as Benign. ClinVar VariationId is 257408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

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.822C>T	p.Ala274Ala	synonymous	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.822C>T	p.Ala274Ala	synonymous	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.822C>T	p.Ala274Ala	synonymous	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.822C>T	p.Ala274Ala	synonymous	Exon 3 of 3	ENSP00000362305.1	P14222
	PALD1	ENST00000697571.1		c.2430G>A	p.Ser810Ser	synonymous	Exon 20 of 21	ENSP00000513342.1	A0A8V8TMP9

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23670 AN: 152134 Hom.: 2188 Cov.: 33

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0831

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.164 AC: 41221 AN: 251390 AF XY: 0.160

Gnomad AFR exome AF: 0.0769

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.179 AC: 261665 AN: 1461884 Hom.: 24634 Cov.: 40 AF XY: 0.176 AC XY: 127861 AN XY: 727242

African (AFR) AF: 0.0761 AC: 2549 AN: 33480

American (AMR) AF: 0.145 AC: 6483 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5406 AN: 26136

East Asian (EAS) AF: 0.119 AC: 4736 AN: 39700

South Asian (SAS) AF: 0.0801 AC: 6910 AN: 86256

European-Finnish (FIN) AF: 0.276 AC: 14718 AN: 53414

Middle Eastern (MID) AF: 0.142 AC: 818 AN: 5768

European-Non Finnish (NFE) AF: 0.189 AC: 210017 AN: 1112010

Other (OTH) AF: 0.166 AC: 10028 AN: 60396

GnomAD4 genome AF: 0.155 AC: 23666 AN: 152252 Hom.: 2187 Cov.: 33 AF XY: 0.157 AC XY: 11708 AN XY: 74446

African (AFR) AF: 0.0807 AC: 3354 AN: 41552

American (AMR) AF: 0.151 AC: 2314 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3470

East Asian (EAS) AF: 0.115 AC: 595 AN: 5182

South Asian (SAS) AF: 0.0830 AC: 401 AN: 4832

European-Finnish (FIN) AF: 0.292 AC: 3088 AN: 10586

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12754 AN: 68004

Other (OTH) AF: 0.145 AC: 306 AN: 2114

Alfa AF: 0.173 Hom.: 2587

Bravo AF: 0.141

Asia WGS AF: 0.102 AC: 353 AN: 3478

EpiCase AF: 0.181

EpiControl AF: 0.175

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.31
DANN	Benign	0.69
PhyloP100		-3.4
Mutation Taster		=97/3	polymorphism (auto)

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: rs885821; hg19: chr10-72358655; COSMIC: COSV64614345;