chr12-6334131-G-C

Position:

• chr12-6334131-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001065.4(TNFRSF1A):​c.153C>G​(p.His51Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H51R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.39

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a repeat TNFR-Cys 1 (size 39) in uniprot entity TNR1A_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_001065.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6334132-T-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.153C>G	p.His51Gln	missense_variant	2/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346092.2	c.-425C>G		5_prime_UTR_variant	2/11		NP_001333021.1
TNFRSF1A	NM_001346091.2	c.-131-266C>G		intron_variant			NP_001333020.1
TNFRSF1A	NR_144351.2	n.415C>G		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.153C>G	p.His51Gln	missense_variant	2/10	1	NM_001065.4	ENSP00000162749	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;D;.;D;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Uncertain	2.7	M;.;.;M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;T;D;T;D;D
Sift4G	Uncertain	0.0070	D;D;.;D;.;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.62
MutPred		0.74		Gain of catalytic residue at P52 (P = 2e-04);Gain of catalytic residue at P52 (P = 2e-04);Gain of catalytic residue at P52 (P = 2e-04);Gain of catalytic residue at P52 (P = 2e-04);Gain of catalytic residue at P52 (P = 2e-04);Gain of catalytic residue at P52 (P = 2e-04);
MVP		0.99
MPC		1.5
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.74
gMVP		0.98

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: rs104895254; hg19: chr12-6443297;