rs1800693

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001065.4(TNFRSF1A):c.625+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,611,606 control chromosomes in the GnomAD database, including 123,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 10910 hom., cov: 30)

Exomes 𝑓: 0.39 ( 112398 hom. )

Consequence

TNFRSF1A
NM_001065.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:3B:10O:2

Conservation

PhyloP100: 0.172

Variant links:

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]

TNFRSF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-6330843-T-C is Benign according to our data. Variant chr12-6330843-T-C is described in ClinVar as [Benign]. Clinvar id is 37038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6330843-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
TNFRSF1A	NM_001065.4 linkuse as main transcript	c.625+10A>G	intron_variant	ENST00000162749.7
TNFRSF1A	NM_001346091.2 linkuse as main transcript	c.301+10A>G	intron_variant
TNFRSF1A	NM_001346092.2 linkuse as main transcript	c.166+10A>G	intron_variant
TNFRSF1A	NR_144351.2 linkuse as main transcript	n.814-132A>G	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7 linkuse as main transcript	c.625+10A>G		intron_variant		1	NM_001065.4	P1	P19438-1

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

56939

AN:

151700

Hom.:

10912

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.374

Gnomad AMR

AF:

0.354

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.420

Gnomad NFE

AF:

0.412

Gnomad OTH

AF:

0.361

GnomAD3 exomes

AF:

0.361

AC:

90633

AN:

251114

Hom.:

17154

AF XY:

0.361

AC XY:

49021

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.141

Gnomad SAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.407

Gnomad NFE exome

AF:

0.408

Gnomad OTH exome

AF:

0.379

GnomAD4 exome

AF:

0.388

AC:

566393

AN:

1459786

Hom.:

112398

Cov.:

AF XY:

0.387

AC XY:

281181

AN XY:

726316

show subpopulations

Gnomad4 AFR exome

AF:

0.350

Gnomad4 AMR exome

AF:

0.327

Gnomad4 ASJ exome

AF:

0.401

Gnomad4 EAS exome

AF:

0.159

Gnomad4 SAS exome

AF:

0.313

Gnomad4 FIN exome

AF:

0.412

Gnomad4 NFE exome

AF:

0.405

Gnomad4 OTH exome

AF:

0.372

GnomAD4 genome

AF:

0.375

AC:

56939

AN:

151820

Hom.:

10910

Cov.:

AF XY:

0.374

AC XY:

27718

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.348

Gnomad4 AMR

AF:

0.354

Gnomad4 ASJ

AF:

0.413

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.302

Gnomad4 FIN

AF:

0.414

Gnomad4 NFE

AF:

0.412

Gnomad4 OTH

AF:

0.359

Alfa

AF:

0.397

Hom.:

27307

Bravo

AF:

0.368

Asia WGS

AF:

0.230

AC:

800

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 53. Only high quality variants are reported. -
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, one paper claims association with MS -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24174586, 22801493, 23624563) -
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. -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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 TNFR6

Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Aug 07, 2021

NA -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Multiple sclerosis, susceptibility to, 5

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 23, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

Dann

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over