chr12-6341412-A-G

Variant names:

• chr12-6341412-A-G
• rs4149623
• NM_001065.4:c.39+364T>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+364T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,162 control chromosomes in the GnomAD database, including 4,877 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 0.15 (4877 hom., cov: 32)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.33
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.39+364T>C		intron_variant	Intron 1 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-132+364T>C		intron_variant	Intron 1 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-539+364T>C		intron_variant	Intron 1 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2	n.301+364T>C		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+364T>C		intron_variant	Intron 1 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23101 AN: 152044 Hom.: 4865 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.0879

Gnomad SAS AF: 0.0384

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00907

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.152 AC: 23154 AN: 152162 Hom.: 4877 Cov.: 32 AF XY: 0.150 AC XY: 11174 AN XY: 74396

African (AFR) AF: 0.471 AC: 19536 AN: 41472

American (AMR) AF: 0.123 AC: 1878 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3472

East Asian (EAS) AF: 0.0881 AC: 455 AN: 5164

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4818

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.00904 AC: 615 AN: 68004

Other (OTH) AF: 0.129 AC: 272 AN: 2116

Alfa AF: 0.0594 Hom.: 1029

Bravo AF: 0.174

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.13
DANN	Benign	0.19
PhyloP100		-3.3
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4149623; hg19: chr12-6450578;