chr12-6340218-C-G

Variant names:

• chr12-6340218-C-G
• rs4149573
• NM_001065.4:c.39+1558G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001065.4(TNFRSF1A):​c.39+1558G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 152,254 control chromosomes in the GnomAD database, including 693 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.091 (693 hom., cov: 32)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.949
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

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.39+1558G>C		intron	N/A	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.-132+1558G>C		intron	N/A	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.-539+1558G>C		intron	N/A	NP_001333021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.39+1558G>C		intron	N/A	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.39+1558G>C		intron	N/A	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.73+1558G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0910 AC: 13848 AN: 152136 Hom.: 689 Cov.: 32

Gnomad AFR AF: 0.0855

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0841

Gnomad OTH AF: 0.0837

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0911 AC: 13863 AN: 152254 Hom.: 693 Cov.: 32 AF XY: 0.0942 AC XY: 7015 AN XY: 74440

African (AFR) AF: 0.0856 AC: 3557 AN: 41556

American (AMR) AF: 0.0611 AC: 934 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0536 AC: 186 AN: 3470

East Asian (EAS) AF: 0.148 AC: 766 AN: 5182

South Asian (SAS) AF: 0.217 AC: 1049 AN: 4830

European-Finnish (FIN) AF: 0.137 AC: 1447 AN: 10592

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0841 AC: 5723 AN: 68016

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.0933 Hom.: 99

Bravo AF: 0.0836

Asia WGS AF: 0.172 AC: 600 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4149573; hg19: chr12-6449384;