12-6336816-A-C

Position:

• chr12-6336816-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001065.4(TNFRSF1A):​c.40-2572T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,038 control chromosomes in the GnomAD database, including 28,591 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 0.60 (28591 hom., cov: 33)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.40-2572T>G		intron_variant		ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-131-2951T>G		intron_variant
TNFRSF1A	NM_001346092.2	c.-538-2572T>G		intron_variant
TNFRSF1A	NR_144351.2	n.302-2572T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.40-2572T>G		intron_variant		1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91205 AN: 151920 Hom.: 28566 Cov.: 33

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.563

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

GnomAD4 genome AF: 0.600 AC: 91279 AN: 152038 Hom.: 28591 Cov.: 33 AF XY: 0.601 AC XY: 44662 AN XY: 74332

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.515

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.566

Alfa AF: 0.509 Hom.: 3320

Bravo AF: 0.599

Asia WGS AF: 0.504 AC: 1756 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	13
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs887477; hg19: chr12-6445982;