chr12-6339949-C-T

Variant names:

• chr12-6339949-C-T
• rs4149576
• NM_001065.4:c.39+1827G>A

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+1827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 151,816 control chromosomes in the GnomAD database, including 9,336 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 0.32 (9336 hom., cov: 30)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280
• Publications: 42 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 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.39+1827G>A		intron	N/A	NP_001056.1
	TNFRSF1A	NM_001346091.2		c.-132+1827G>A		intron	N/A	NP_001333020.1
	TNFRSF1A	NM_001346092.2		c.-539+1827G>A		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.39+1827G>A		intron	N/A	ENSP00000162749.2
	TNFRSF1A	ENST00000540022.5	TSL:1	c.39+1827G>A		intron	N/A	ENSP00000438343.1
	TNFRSF1A	ENST00000366159.9	TSL:1	n.73+1827G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49084 AN: 151698 Hom.: 9343 Cov.: 30

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.323 AC: 49074 AN: 151816 Hom.: 9336 Cov.: 30 AF XY: 0.323 AC XY: 23961 AN XY: 74158

African (AFR) AF: 0.128 AC: 5282 AN: 41384

American (AMR) AF: 0.336 AC: 5115 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1464 AN: 3468

East Asian (EAS) AF: 0.135 AC: 697 AN: 5154

South Asian (SAS) AF: 0.284 AC: 1365 AN: 4800

European-Finnish (FIN) AF: 0.436 AC: 4594 AN: 10528

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29363 AN: 67936

Other (OTH) AF: 0.328 AC: 690 AN: 2104

Alfa AF: 0.400 Hom.: 21327

Bravo AF: 0.305

Asia WGS AF: 0.211 AC: 735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.51
PhyloP100		0.028
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: rs4149576; hg19: chr12-6449115;