rs4149572

Positions:

• chr12-6340577-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001065.4(TNFRSF1A):​c.39+1199G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 152,066 control chromosomes in the GnomAD database, including 78 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 0.025 (78 hom., cov: 32)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152

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=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0252 (3838/152066) while in subpopulation NFE AF= 0.0357 (2427/67974). AF 95% confidence interval is 0.0345. There are 78 homozygotes in gnomad4. There are 1848 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3838 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.39+1199G>T		intron_variant		ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-132+1199G>T		intron_variant
TNFRSF1A	NM_001346092.2	c.-539+1199G>T		intron_variant
TNFRSF1A	NR_144351.2	n.301+1199G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.39+1199G>T		intron_variant		1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3838 AN: 151948 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00559

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0397

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

GnomAD4 genome AF: 0.0252 AC: 3838 AN: 152066 Hom.: 78 Cov.: 32 AF XY: 0.0249 AC XY: 1848 AN XY: 74332

Gnomad4 AFR AF: 0.00560

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0879

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0357

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0344 Hom.: 40

Bravo AF: 0.0261

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99

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: rs4149572; hg19: chr12-6449743;