rs139298157

Variant names:

• chr10-70597687-G-A
• rs139298157
• NM_001083116.3:c.*366C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70597687-G-A
• chr10-70597687-G-C
• chr10-70597687-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001083116.3(PRF1):​c.*366C>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 0.00138 in 595,228 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0660
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046587884).
• BP6: Variant 10-70597687-G-A is Benign according to our data. Variant chr10-70597687-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 879861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00388 (590/152230) while in subpopulation AFR AF = 0.0139 (579/41532). AF 95% confidence interval is 0.013. There are 4 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 Unknown,AR 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.*366C>T		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*366C>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.*366C>T		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*366C>T		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000638674.1	TSL:5	c.694C>T	p.Arg232Cys	missense	Exon 3 of 3	ENSP00000492048.1	A0A1W2PR25

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 585 AN: 152112 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000521 AC: 231 AN: 442998 Hom.: 2 Cov.: 0 AF XY: 0.000411 AC XY: 96 AN XY: 233478

African (AFR) AF: 0.0151 AC: 186 AN: 12316

American (AMR) AF: 0.000632 AC: 11 AN: 17410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13588

East Asian (EAS) AF: 0.00 AC: 0 AN: 30794

South Asian (SAS) AF: 0.0000708 AC: 3 AN: 42396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1966

European-Non Finnish (NFE) AF: 0.00000743 AC: 2 AN: 269348

Other (OTH) AF: 0.00113 AC: 29 AN: 25738

GnomAD4 genome AF: 0.00388 AC: 590 AN: 152230 Hom.: 4 Cov.: 32 AF XY: 0.00374 AC XY: 278 AN XY: 74428

African (AFR) AF: 0.0139 AC: 579 AN: 41532

American (AMR) AF: 0.000458 AC: 7 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00231 Hom.: 1

Bravo AF: 0.00413

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hemophagocytic lymphohistiocytosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.2
DANN	Benign	0.50
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0047	T
PhyloP100		-0.066
GERP RS		-2.9
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: rs139298157; hg19: chr10-72357443;