12-6338271-C-T

Variant names:

• chr12-6338271-C-T
• rs4149578
• NM_001065.4:c.39+3505G>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+3505G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 151,904 control chromosomes in the GnomAD database, including 2,315 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 0.16 (2315 hom., cov: 31)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.699
• Publications: 24 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 (AFR) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.39+3505G>A		intron_variant	Intron 1 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-132+3505G>A		intron_variant	Intron 1 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-539+3505G>A		intron_variant	Intron 1 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2	n.301+3505G>A		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+3505G>A		intron_variant	Intron 1 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23764 AN: 151786 Hom.: 2313 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0972

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0912

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.157 AC: 23804 AN: 151904 Hom.: 2315 Cov.: 31 AF XY: 0.161 AC XY: 11981 AN XY: 74278

African (AFR) AF: 0.264 AC: 10933 AN: 41346

American (AMR) AF: 0.140 AC: 2140 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0972 AC: 337 AN: 3468

East Asian (EAS) AF: 0.226 AC: 1166 AN: 5150

South Asian (SAS) AF: 0.252 AC: 1211 AN: 4814

European-Finnish (FIN) AF: 0.140 AC: 1484 AN: 10584

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0911 AC: 6195 AN: 67972

Other (OTH) AF: 0.143 AC: 301 AN: 2106

Alfa AF: 0.104 Hom.: 640

Bravo AF: 0.159

Asia WGS AF: 0.250 AC: 871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.80
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4149578; hg19: chr12-6447437;