12-6337611-G-A

Variant names:

• chr12-6337611-G-A
• rs1860545
• NM_001065.4:c.40-3367C>T

Variant summary

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

The NM_001065.4(TNFRSF1A):​c.40-3367C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,012 control chromosomes in the GnomAD database, including 8,383 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 0.31 (8383 hom., cov: 31)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• Publications: 44 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	NM_001065.4	MANE Select	c.40-3367C>T		intron	N/A	NP_001056.1
	TNFRSF1A	NM_001346091.2		c.-131-3746C>T		intron	N/A	NP_001333020.1
	TNFRSF1A	NM_001346092.2		c.-538-3367C>T		intron	N/A	NP_001333021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.40-3367C>T		intron	N/A	ENSP00000162749.2
	TNFRSF1A	ENST00000540022.5	TSL:1	c.40-3367C>T		intron	N/A	ENSP00000438343.1
	TNFRSF1A	ENST00000366159.9	TSL:1	n.74-3367C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46499 AN: 151894 Hom.: 8388 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.302

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

GnomAD4 genome AF: 0.306 AC: 46490 AN: 152012 Hom.: 8383 Cov.: 31 AF XY: 0.307 AC XY: 22811 AN XY: 74278

African (AFR) AF: 0.116 AC: 4823 AN: 41480

American (AMR) AF: 0.317 AC: 4847 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3468

East Asian (EAS) AF: 0.135 AC: 699 AN: 5184

South Asian (SAS) AF: 0.285 AC: 1373 AN: 4826

European-Finnish (FIN) AF: 0.421 AC: 4442 AN: 10548

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.410 AC: 27825 AN: 67930

Other (OTH) AF: 0.300 AC: 633 AN: 2108

Alfa AF: 0.363 Hom.: 25887

Bravo AF: 0.287

Asia WGS AF: 0.208 AC: 723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.70
PhyloP100		-0.016
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: rs1860545; hg19: chr12-6446777;