12-6329603-C-G

Variant names:

• chr12-6329603-C-G
• NM_001065.4:c.1077G>C
• TNFRSF1A p.Leu359Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001065.4(TNFRSF1A):​c.1077G>C​(p.Leu359Leu) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L359L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF1A NM_001065.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• 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: Illumina, PanelApp Australia, ClinGen, Laboratory for Molecular Medicine, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=0.06 with no splicing effect.

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.1077G>C	p.Leu359Leu	synonymous	Exon 10 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.753G>C	p.Leu251Leu	synonymous	Exon 9 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.618G>C	p.Leu206Leu	synonymous	Exon 11 of 11	NP_001333021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.1077G>C	p.Leu359Leu	synonymous	Exon 10 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.948G>C	p.Leu316Leu	synonymous	Exon 9 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.2178G>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.2
DANN	Benign	0.81
PhyloP100		0.060
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-6438769;