12-6339949-C-T

Position:

• chr12-6339949-C-T

Variant summary

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

The ENST00000162749.7(TNFRSF1A):​c.39+1827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 151,816 control chromosomes in the GnomAD database, including 9,336 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 0.32 (9336 hom., cov: 30)
• Consequence: TNFRSF1A ENST00000162749.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.39+1827G>A		intron_variant		ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.-132+1827G>A		intron_variant			NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-539+1827G>A		intron_variant			NP_001333021.1
TNFRSF1A	NR_144351.2	n.301+1827G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+1827G>A		intron_variant		1	NM_001065.4	ENSP00000162749	P1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49084 AN: 151698 Hom.: 9343 Cov.: 30

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.323 AC: 49074 AN: 151816 Hom.: 9336 Cov.: 30 AF XY: 0.323 AC XY: 23961 AN XY: 74158

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.328

Alfa AF: 0.409 Hom.: 17436

Bravo AF: 0.305

Asia WGS AF: 0.211 AC: 735 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	2.7
DANN	Benign	0.51

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: rs4149576; hg19: chr12-6449115;