rs12426675

chr12-6330304-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001065.4(TNFRSF1A):c.740-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,464 control chromosomes in the GnomAD database, including 49,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5239 hom., cov: 32)
  • Exomes 𝑓: 0.23 (43930 hom.)
• Consequence: TNFRSF1A NM_001065.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009474
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-6330304-A-G is Benign according to our data. Variant chr12-6330304-A-G is described in ClinVar as [Benign]. Clinvar id is 257327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6330304-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.740-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.416-9T>C		splice_polypyrimidine_tract_variant, intron_variant
TNFRSF1A	NM_001346092.2	c.281-9T>C		splice_polypyrimidine_tract_variant, intron_variant
TNFRSF1A	NR_144351.2	n.928-9T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.740-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38810 AN: 151976 Hom.: 5227 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.280 AC: 70416 AN: 251338 Hom.: 11062 AF XY: 0.283 AC XY: 38488 AN XY: 135878

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.235 AC: 342319 AN: 1459370 Hom.: 43930 Cov.: 32 AF XY: 0.240 AC XY: 174134 AN XY: 726140

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.255 AC: 38854 AN: 152094 Hom.: 5239 Cov.: 32 AF XY: 0.261 AC XY: 19389 AN XY: 74328

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.287

Alfa AF: 0.229 Hom.: 3528

Bravo AF: 0.262

Asia WGS AF: 0.390 AC: 1358 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

TNF receptor-associated periodic fever syndrome (TRAPS) Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	12
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000095
dbscSNV1_RF	Benign	0.040
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: rs12426675; hg19: chr12-6439470; COSMIC: COSV50598650; COSMIC: COSV50598650;