rs1555107565

chr12-6330687-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001065.4(TNFRSF1A):c.650T>C(p.Val217Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.650T>C	p.Val217Ala	missense_variant	7/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.326T>C	p.Val109Ala	missense_variant	6/9
TNFRSF1A	NM_001346092.2	c.191T>C	p.Val64Ala	missense_variant	8/11
TNFRSF1A	NR_144351.2	n.838T>C		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.650T>C	p.Val217Ala	missense_variant	7/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Jan 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	0.43	D
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.24	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.66
MutPred		0.47		Gain of catalytic residue at L222 (P = 0);.;Gain of catalytic residue at L222 (P = 0);
MVP		0.87
MPC		1.7
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.89

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: rs1555107565; hg19: chr12-6439853;