NM_001083116.3:c.539+22G>C

Variant names:

• chr10-70600342-C-G
• rs12263464
• NM_001083116.3:c.539+22G>C

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.539+22G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,613,846 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (122 hom.)
• Consequence: PRF1 NM_001083116.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.909
• Publications: 0 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 10-70600342-C-G is Benign according to our data. Variant chr10-70600342-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0729 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.539+22G>C		intron	N/A	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.539+22G>C		intron	N/A	NP_005032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRF1	ENST00000441259.2	TSL:5 MANE Select	c.539+22G>C		intron	N/A	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.539+22G>C		intron	N/A	ENSP00000362305.1	P14222
	PALD1	ENST00000697571.1		c.*17+1258C>G		intron	N/A	ENSP00000513342.1	A0A8V8TMP9

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3347 AN: 152098 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.00637 AC: 1591 AN: 249842 AF XY: 0.00461

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000427

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00259 AC: 3783 AN: 1461630 Hom.: 122 Cov.: 34 AF XY: 0.00228 AC XY: 1660 AN XY: 727102

African (AFR) AF: 0.0821 AC: 2746 AN: 33466

American (AMR) AF: 0.00559 AC: 250 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00681 AC: 178 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000158 AC: 176 AN: 1111982

Other (OTH) AF: 0.00659 AC: 398 AN: 60390

GnomAD4 genome AF: 0.0221 AC: 3358 AN: 152216 Hom.: 97 Cov.: 32 AF XY: 0.0217 AC XY: 1613 AN XY: 74422

African (AFR) AF: 0.0751 AC: 3116 AN: 41510

American (AMR) AF: 0.0102 AC: 156 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68014

Other (OTH) AF: 0.0209 AC: 44 AN: 2108

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.0260

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.038
DANN	Benign	0.41
PhyloP100		-0.91
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: rs12263464; hg19: chr10-72360098;