chr12-6329060-T-C

Variant names:

• chr12-6329060-T-C
• rs45563431
• NM_001065.4:c.*252A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001065.4(TNFRSF1A):​c.*252A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 408,196 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (2 hom.)
• Consequence: TNFRSF1A NM_001065.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.14

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=-0.9).
• BP6: Variant 12-6329060-T-C is Benign according to our data. Variant chr12-6329060-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 883007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000512 (78/152370) while in subpopulation EAS AF= 0.0056 (29/5182). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.*252A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.*252A>G		3_prime_UTR_variant	Exon 9 of 9		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.*252A>G		3_prime_UTR_variant	Exon 11 of 11		NP_001333021.1
TNFRSF1A	NR_144351.2	n.1808A>G		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749	c.*252A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000868 AC: 222 AN: 255826 Hom.: 2 Cov.: 4 AF XY: 0.000816 AC XY: 106 AN XY: 129910

Gnomad4 AFR exome AF: 0.000280

Gnomad4 AMR exome AF: 0.000130

Gnomad4 ASJ exome AF: 0.000108

Gnomad4 EAS exome AF: 0.00460

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74506

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.000442

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNFRSF1A: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.077
DANN	Benign	0.51
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: rs45563431; hg19: chr12-6438226;