12-6338271-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (AFR) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.39+3505G>A		intron_variant		ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-132+3505G>A		intron_variant
TNFRSF1A	NM_001346092.2	c.-539+3505G>A		intron_variant
TNFRSF1A	NR_144351.2	n.301+3505G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+3505G>A		intron_variant		1	NM_001065.4	P1

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

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.0972

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.0911

Gnomad4 OTH AF: 0.143

Alfa AF: 0.103 Hom.: 589

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
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: rs4149578; hg19: chr12-6447437;