12-6330882-A-T

Variant names:

• chr12-6330882-A-T
• rs104895247
• NM_001065.4:c.596T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001065.4(TNFRSF1A):​c.596T>A​(p.Ile199Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: -0.227

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 12 ACMG points.

• PM1: In a chain Tumor necrosis factor-binding protein 1 (size 160) in uniprot entity TNR1A_HUMAN there are 73 pathogenic changes around while only 1 benign (99%) in NM_001065.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-6330882-A-T is Pathogenic according to our data. Variant chr12-6330882-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6330882-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.596T>A	p.Ile199Asn	missense_variant	Exon 6 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.272T>A	p.Ile91Asn	missense_variant	Exon 5 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.137T>A	p.Ile46Asn	missense_variant	Exon 7 of 11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.814-171T>A		intron_variant	Intron 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.596T>A	p.Ile199Asn	missense_variant	Exon 6 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

-

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 10, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	0.40
DANN	Benign	0.56
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.064	T;T;.
Polyphen		0.045	B;B;.
Vest4		0.25
MutPred		0.80		Gain of catalytic residue at L196 (P = 2e-04);.;Gain of catalytic residue at L196 (P = 2e-04);
MVP		0.91
MPC		1.0
ClinPred		0.081	T
GERP RS		-4.8
Varity_R		0.28
gMVP		0.86

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: rs104895247; hg19: chr12-6440048;