rs104895219

chr12-6333823-G-Achr12-6333823-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001065.4(TNFRSF1A):c.236C>T(p.Thr79Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T79K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 5.88

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001065.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 12-6333823-G-A is Pathogenic according to our data. Variant chr12-6333823-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6333823-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.236C>T	p.Thr79Met	missense_variant	3/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-89C>T		5_prime_UTR_variant	2/9
TNFRSF1A	NM_001346092.2	c.-342C>T		5_prime_UTR_variant	3/11
TNFRSF1A	NR_144351.2	n.498C>T		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.236C>T	p.Thr79Met	missense_variant	3/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444640 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 717094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Dec 23, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 1999	- -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 79 of the TNFRSF1A protein (p.Thr79Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TNF receptor-associated periodic fever syndrome (PMID: 10199409, 13130484, 23965844, 24393624, 25936627). It has also been observed to segregate with disease in related individuals. This variant is also known as T50M. ClinVar contains an entry for this variant (Variation ID: 12336). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNFRSF1A protein function. Experimental studies have shown that this missense change affects TNFRSF1A function (PMID: 15312137, 20457915). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	Published functional studies demonstrate a damaging effect due to cytoplasmic retention, reduced protein surface expression, impaired binding of TNF-alpha, and activation of the TNF-R1 and inflammasome pathways (Todd et al., 2004; Greco et al., 2015).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T50M); This variant is associated with the following publications: (PMID: 24950168, 25888769, 24393624, 26598380, 21153350, 16684962, 15312137, 21282379, 23894535, 20457915, 10199409, 25936627, 27332769, 33440462, 11722598, 31586650, 33284430, 31562507, 35577052, 15570662, 23965844) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;D;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.019	D;.;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.54
MutPred		0.82		Gain of catalytic residue at G74 (P = 0.0014);Gain of catalytic residue at G74 (P = 0.0014);Gain of catalytic residue at G74 (P = 0.0014);Gain of catalytic residue at G74 (P = 0.0014);.;
MVP		0.97
MPC		1.6
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.95

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: rs104895219; hg19: chr12-6442989; COSMIC: COSV50829611; COSMIC: COSV50829611;