rs116554195

chr10-70600441-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083116.3(PRF1):c.462A>G(p.Ala154=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,614,242 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (63 hom.)
• Consequence: PRF1 NM_001083116.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.13

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-70600441-T-C is Benign according to our data. Variant chr10-70600441-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2138/152352) while in subpopulation AFR AF= 0.0321 (1336/41586). AF 95% confidence interval is 0.0307. There are 29 homozygotes in gnomad4. There are 978 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRF1	NM_001083116.3	c.462A>G	p.Ala154=	synonymous_variant	2/3	ENST00000441259.2
PRF1	NM_005041.6	c.462A>G	p.Ala154=	synonymous_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRF1	ENST00000441259.2	c.462A>G	p.Ala154=	synonymous_variant	2/3	5	NM_001083116.3	P1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2132 AN: 152234 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00679 AC: 1706 AN: 251418 Hom.: 16 AF XY: 0.00600 AC XY: 816 AN XY: 135894

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00546

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00695 AC: 10159 AN: 1461890 Hom.: 63 Cov.: 34 AF XY: 0.00678 AC XY: 4932 AN XY: 727246

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00536

Gnomad4 FIN exome AF: 0.000786

Gnomad4 NFE exome AF: 0.00696

Gnomad4 OTH exome AF: 0.00772

GnomAD4 genome AF: 0.0140 AC: 2138 AN: 152352 Hom.: 29 Cov.: 32 AF XY: 0.0131 AC XY: 978 AN XY: 74510

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00698

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00915 Hom.: 4

Bravo AF: 0.0159

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hemophagocytic lymphohistiocytosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2020

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.8
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs116554195; hg19: chr10-72360197;