12-6329331-G-C

Position:

• chr12-6329331-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001065.4(TNFRSF1A):​c.1349C>G​(p.Ala450Gly) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.137

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05910504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.1349C>G	p.Ala450Gly	missense_variant	10/10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.1025C>G	p.Ala342Gly	missense_variant	9/9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.890C>G	p.Ala297Gly	missense_variant	11/11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.1537C>G		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.1349C>G	p.Ala450Gly	missense_variant	10/10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 2 AN: 1322214 Hom.: 0 Cov.: 31 AF XY: 0.00000309 AC XY: 2 AN XY: 647212

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: 0.0000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.48e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2022

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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt TNFRSF1A protein function. ClinVar contains an entry for this variant (Variation ID: 1055756). This variant has not been reported in the literature in individuals affected with TNFRSF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 450 of the TNFRSF1A protein (p.Ala450Gly). -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	1.6
DANN	Benign	0.57
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.34	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	B;B
Vest4		0.071
MutPred		0.17		Gain of catalytic residue at P448 (P = 8e-04);.;
MVP		0.75
MPC		0.57
ClinPred		0.17	T
GERP RS		-3.8
Varity_R		0.056
gMVP		0.084

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: rs1426121771; hg19: chr12-6438497;