rs4149572

Variant names:

• chr12-6340577-C-A
• rs4149572
• NM_001065.4:c.39+1199G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001065.4(TNFRSF1A):​c.39+1199G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 152,066 control chromosomes in the GnomAD database, including 78 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 0.025 (78 hom., cov: 32)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• Publications: 2 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=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0252 (3838/152066) while in subpopulation NFE AF = 0.0357 (2427/67974). AF 95% confidence interval is 0.0345. There are 78 homozygotes in GnomAd4. There are 1848 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3838 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.39+1199G>T		intron_variant	Intron 1 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-132+1199G>T		intron_variant	Intron 1 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-539+1199G>T		intron_variant	Intron 1 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2	n.301+1199G>T		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+1199G>T		intron_variant	Intron 1 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3838 AN: 151948 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00559

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0397

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

GnomAD4 genome AF: 0.0252 AC: 3838 AN: 152066 Hom.: 78 Cov.: 32 AF XY: 0.0249 AC XY: 1848 AN XY: 74332

African (AFR) AF: 0.00560 AC: 232 AN: 41460

American (AMR) AF: 0.0290 AC: 442 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 305 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4818

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10584

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2427 AN: 67974

Other (OTH) AF: 0.0393 AC: 83 AN: 2114

Alfa AF: 0.0341 Hom.: 58

Bravo AF: 0.0261

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.78
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99
Mutation Taster		=100/0	polymorphism

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: rs4149572; hg19: chr12-6449743;