rs1139417

chr12-6341779-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001065.4(TNFRSF1A):c.36A>G(p.Pro12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,612 control chromosomes in the GnomAD database, including 135,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12088 hom., cov: 33)
  • Exomes 𝑓: 0.41 (123613 hom.)
• Consequence: TNFRSF1A NM_001065.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:3 B:9 O:1
• Conservation: PhyloP100: -0.107

Genes affected

TNFRSF1A (HGNC:11916): (TNF receptor superfamily member 1A) This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-6341779-T-C is Benign according to our data. Variant chr12-6341779-T-C is described in ClinVar as [Benign]. Clinvar id is 257326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6341779-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.107 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.36A>G	p.Pro12=	synonymous_variant	1/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-135A>G		5_prime_UTR_variant	1/9
TNFRSF1A	NM_001346092.2	c.-542A>G		5_prime_UTR_variant	1/11
TNFRSF1A	NR_144351.2	n.298A>G		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.36A>G	p.Pro12=	synonymous_variant	1/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59765 AN: 152026 Hom.: 12096 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.382

GnomAD3 exomes AF: 0.374 AC: 93640 AN: 250294 Hom.: 18566 AF XY: 0.374 AC XY: 50626 AN XY: 135412

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.406 AC: 593442 AN: 1461468 Hom.: 123613 Cov.: 46 AF XY: 0.404 AC XY: 293957 AN XY: 727038

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.426

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.393 AC: 59763 AN: 152144 Hom.: 12088 Cov.: 33 AF XY: 0.391 AC XY: 29083 AN XY: 74394

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.380

Alfa AF: 0.422 Hom.: 23914

Bravo AF: 0.383

Asia WGS AF: 0.225 AC: 784 AN: 3478

EpiCase AF: 0.439

EpiControl AF: 0.432

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

TNF receptor-associated periodic fever syndrome (TRAPS) 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 13, 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. -

Associated with severe COVID-19 disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 01, 2023

- -

Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Feb 09, 2021

- -

Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR7 Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Aug 07, 2021

NA -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767455; hg19: chr12-6450945; COSMIC: COSV50827987; COSMIC: COSV50827987;