rs1860545

Positions:

• chr12-6337611-G-A
• chr12-6337611-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001065.4(TNFRSF1A):​c.40-3367C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,012 control chromosomes in the GnomAD database, including 8,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.31 (8383 hom., cov: 31)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-6337611-G-A is Benign according to our data. Variant chr12-6337611-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.40-3367C>T		intron_variant		ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-131-3746C>T		intron_variant			NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-538-3367C>T		intron_variant			NP_001333021.1
TNFRSF1A	NR_144351.2	n.302-3367C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.40-3367C>T		intron_variant		1	NM_001065.4	ENSP00000162749	P1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46499 AN: 151894 Hom.: 8388 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.302

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

GnomAD4 genome AF: 0.306 AC: 46490 AN: 152012 Hom.: 8383 Cov.: 31 AF XY: 0.307 AC XY: 22811 AN XY: 74278

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.300

Alfa AF: 0.373 Hom.: 7413

Bravo AF: 0.287

Asia WGS AF: 0.208 AC: 723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs1860545; hg19: chr12-6446777;