rs6480459

Variant names:

• chr10-70597964-G-A
• rs6480459
• NM_001083116.3:c.*89C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70597964-G-A
• chr10-70597964-G-T

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.*89C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 1,537,796 control chromosomes in the GnomAD database, including 5,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (966 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4453 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.346
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-70597964-G-A is Benign according to our data. Variant chr10-70597964-G-A is described in ClinVar as Benign. ClinVar VariationId is 300325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 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.*89C>T		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*89C>T		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.*89C>T		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*89C>T		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*89C>T		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.0983 AC: 14943 AN: 152022 Hom.: 966 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0886

GnomAD4 exome AF: 0.0752 AC: 104167 AN: 1385656 Hom.: 4453 Cov.: 29 AF XY: 0.0749 AC XY: 51774 AN XY: 691182

African (AFR) AF: 0.176 AC: 5606 AN: 31776

American (AMR) AF: 0.0441 AC: 1875 AN: 42508

Ashkenazi Jewish (ASJ) AF: 0.0744 AC: 1899 AN: 25528

East Asian (EAS) AF: 0.0141 AC: 545 AN: 38568

South Asian (SAS) AF: 0.0687 AC: 5685 AN: 82706

European-Finnish (FIN) AF: 0.0389 AC: 1544 AN: 39688

Middle Eastern (MID) AF: 0.132 AC: 552 AN: 4196

European-Non Finnish (NFE) AF: 0.0772 AC: 82029 AN: 1062590

Other (OTH) AF: 0.0763 AC: 4432 AN: 58096

GnomAD4 genome AF: 0.0983 AC: 14951 AN: 152140 Hom.: 966 Cov.: 32 AF XY: 0.0954 AC XY: 7098 AN XY: 74386

African (AFR) AF: 0.177 AC: 7352 AN: 41500

American (AMR) AF: 0.0583 AC: 892 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 269 AN: 3466

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5174

South Asian (SAS) AF: 0.0691 AC: 332 AN: 4806

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10600

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0795 AC: 5405 AN: 67990

Other (OTH) AF: 0.0882 AC: 186 AN: 2110

Alfa AF: 0.0772 Hom.: 374

Bravo AF: 0.103

Asia WGS AF: 0.0440 AC: 156 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-0.35
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: rs6480459; hg19: chr10-72357720;