NM_001065.4:c.39+3585G>A

Variant names:

• chr12-6338191-C-T
• rs4149579
• NM_001065.4:c.39+3585G>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+3585G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 152,168 control chromosomes in the GnomAD database, including 222 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 0.049 (222 hom., cov: 31)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 20 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.39+3585G>A		intron_variant	Intron 1 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-132+3585G>A		intron_variant	Intron 1 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-539+3585G>A		intron_variant	Intron 1 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2	n.301+3585G>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+3585G>A		intron_variant	Intron 1 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 7476 AN: 152050 Hom.: 222 Cov.: 31

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0755

Gnomad OTH AF: 0.0522

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

GnomAD4 genome AF: 0.0491 AC: 7469 AN: 152168 Hom.: 222 Cov.: 31 AF XY: 0.0465 AC XY: 3461 AN XY: 74410

African (AFR) AF: 0.0140 AC: 580 AN: 41520

American (AMR) AF: 0.0389 AC: 595 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4818

European-Finnish (FIN) AF: 0.0581 AC: 616 AN: 10594

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5128 AN: 67972

Other (OTH) AF: 0.0507 AC: 107 AN: 2110

Alfa AF: 0.0656 Hom.: 208

Bravo AF: 0.0466

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		0.0010
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4149579; hg19: chr12-6447357;