NM_001083116.3:c.*96G>A

Variant names:

• chr10-70597957-C-T
• rs1889490
• NM_001083116.3:c.*96G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083116.3(PRF1):​c.*96G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,519,626 control chromosomes in the GnomAD database, including 148,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21458 hom., cov: 32)
  • Exomes 𝑓: 0.43 (127383 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.754
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-70597957-C-T is Benign according to our data. Variant chr10-70597957-C-T is described in ClinVar as Benign. ClinVar VariationId is 300324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 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.*96G>A		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*96G>A		3_prime_UTR	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.*96G>A		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*96G>A		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*96G>A		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77439 AN: 151856 Hom.: 21422 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.492

GnomAD4 exome AF: 0.425 AC: 581328 AN: 1367652 Hom.: 127383 Cov.: 24 AF XY: 0.427 AC XY: 291319 AN XY: 682110

African (AFR) AF: 0.740 AC: 23202 AN: 31336

American (AMR) AF: 0.528 AC: 21809 AN: 41288

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9223 AN: 25410

East Asian (EAS) AF: 0.610 AC: 23190 AN: 38000

South Asian (SAS) AF: 0.516 AC: 42189 AN: 81798

European-Finnish (FIN) AF: 0.365 AC: 14181 AN: 38854

Middle Eastern (MID) AF: 0.504 AC: 2062 AN: 4094

European-Non Finnish (NFE) AF: 0.400 AC: 419754 AN: 1049370

Other (OTH) AF: 0.447 AC: 25718 AN: 57502

GnomAD4 genome AF: 0.510 AC: 77540 AN: 151974 Hom.: 21458 Cov.: 32 AF XY: 0.509 AC XY: 37828 AN XY: 74274

African (AFR) AF: 0.734 AC: 30417 AN: 41458

American (AMR) AF: 0.492 AC: 7517 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3470

East Asian (EAS) AF: 0.617 AC: 3174 AN: 5144

South Asian (SAS) AF: 0.513 AC: 2463 AN: 4804

European-Finnish (FIN) AF: 0.362 AC: 3823 AN: 10554

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27283 AN: 67944

Other (OTH) AF: 0.492 AC: 1039 AN: 2112

Alfa AF: 0.475 Hom.: 7400

Bravo AF: 0.533

Asia WGS AF: 0.521 AC: 1815 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial hemophagocytic lymphohistiocytosis 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.32
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs1889490; hg19: chr10-72357713; COSMIC: COSV64614709;