chr12-6333879-C-T

Position:

chr12-6333879-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001065.4(TNFRSF1A):c.194-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,601,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TNFRSF1A
NM_001065.4 intron

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: -1.84

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:

TNFRSF1A (HGNC:):

TNFRSF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 linkuse as main transcript	c.194-14G>A	intron_variant	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2 linkuse as main transcript	c.-131-14G>A	intron_variant		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 linkuse as main transcript	c.-384-14G>A	intron_variant		NP_001333021.1	P19438
TNFRSF1A	NR_144351.2 linkuse as main transcript	n.456-14G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 linkuse as main transcript	c.194-14G>A		intron_variant		1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000142

AC:

AN:

225480

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

121700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000317

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000350

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000270

Gnomad OTH exome

AF:

0.000352

GnomAD4 exome

AF:

0.000184

AC:

266

AN:

1449276

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

128

AN XY:

719910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000236

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000472

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000145

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000788

Hom.:

Bravo

AF:

0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TNFRSF1A: PS4:Moderate, PM4:Supporting, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	Published previously in association with TRAPS; however, the variant was also observed in unaffected family members and in an individual who had a remittance of symptoms (Aksentijevich et al., 2001; D'Osualdo et al., 2006; Stojanov et al., 2008; Gattorno et al., 2008); Functional studies have shown this variant creates a cryptic splice acceptor site, resulting in an insertion of four additional amino acids (Aksentijevich et al., 2001); Reported previously using alternate nomenclature (c.193-14 G>A); This variant is associated with the following publications: (PMID: 12352631, 16508982, 25525159, 15228182, 19541728, 12209523, 18180277, 19877056, 13130484, 33181346, 11443543, 18512793, 28166811) -

TNF receptor-associated periodic fever syndrome (TRAPS)

Uncertain:1Other:1

not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change falls in intron 2 of the TNFRSF1A gene. It does not directly change the encoded amino acid sequence of the TNFRSF1A protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs104895241, gnomAD 0.03%). This variant has been observed in individual(s) with tumor necrosis factor receptor‚Äìassociated periodic syndrome (PMID: 11443543, 18180277). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97654). Studies have shown that this variant results in the activation of a cryptic splice site in intron 3 (PMID: 11443543). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TNFRSF1A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The TNFRSF1A c.194-14G>A variant is predicted to interfere with splicing. This variant is predicted to interfere with normal spicing by activating a cryptic splice acceptor (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). In vitro functional analyses supported this prediction, indicating that aberrant splicing results in the addition of four amino acids (variant described as c.193-14G>A, Aksentijevich et al 2001. PubMed ID: 11443543). This variant was reported in five patients from two families with TNF receptor-associated periodic syndrome (TRAPS) (Aksentijevich et al 2001. PubMed ID: 11443543). It is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect this variant may be pathogenic, at this time the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.40

Position offset: -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