chr10-70597677-C-T

Variant names:

• chr10-70597677-C-T
• rs191816002
• NM_001083116.3:c.*376G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001083116.3(PRF1):​c.*376G>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 0.00165 in 587,542 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: PRF1 NM_001083116.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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.*376G>A		3_prime_UTR	Exon 3 of 3	NP_001076585.1	P14222
	PRF1	NM_005041.6		c.*376G>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.*376G>A		3_prime_UTR	Exon 3 of 3	ENSP00000398568.1	P14222
	PRF1	ENST00000373209.2	TSL:1	c.*376G>A		3_prime_UTR	Exon 3 of 3	ENSP00000362305.1	P14222
	PRF1	ENST00000862973.1		c.*376G>A		3_prime_UTR	Exon 2 of 2	ENSP00000533032.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00168 AC: 731 AN: 435326 Hom.: 1 Cov.: 0 AF XY: 0.00162 AC XY: 372 AN XY: 228946

African (AFR) AF: 0.00123 AC: 15 AN: 12214

American (AMR) AF: 0.000121 AC: 2 AN: 16518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13454

East Asian (EAS) AF: 0.0000329 AC: 1 AN: 30392

South Asian (SAS) AF: 0.0000494 AC: 2 AN: 40508

European-Finnish (FIN) AF: 0.00161 AC: 47 AN: 29220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1942

European-Non Finnish (NFE) AF: 0.00241 AC: 641 AN: 265642

Other (OTH) AF: 0.000904 AC: 23 AN: 25436

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74416

African (AFR) AF: 0.000626 AC: 26 AN: 41538

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00136

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.8
DANN	Benign	0.50
PhyloP100		0.010
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: rs191816002; hg19: chr10-72357433;