12-6334109-A-T

Variant names:

• chr12-6334109-A-T
• rs104895217
• NM_001065.4:c.175T>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong

The NM_001065.4(TNFRSF1A):​c.175T>A​(p.Cys59Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C59F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• TNF receptor 1-associated periodic fever syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Illumina, Laboratory for Molecular Medicine, Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_001065.4 (TNFRSF1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr12-6334108-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97652.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001065.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	NM_001065.4	MANE Select	c.175T>A	p.Cys59Ser	missense	Exon 2 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346092.2		c.-403T>A		5_prime_UTR	Exon 2 of 11	NP_001333021.1
	TNFRSF1A	NM_001346091.2		c.-131-244T>A		intron	N/A	NP_001333020.1	P19438-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.175T>A	p.Cys59Ser	missense	Exon 2 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.175T>A	p.Cys59Ser	missense	Exon 2 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.209T>A		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.88		Gain of catalytic residue at K61 (P = 0)
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.99
gMVP		1.0
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104895217; hg19: chr12-6443275;