12-6330304-A-G

Position:

chr12-6330304-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:9

Conservation

PhyloP100: 1.13

Variant links:

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]

TNFRSF1A links:

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ACMG classification

Classification made for transcript

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	Effect	MANE	Protein
TNFRSF1A	NM_001065.4 linkuse as main transcript	c.740-9T>C	splice_polypyrimidine_tract_variant, intron_variant	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2 linkuse as main transcript	c.416-9T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001333020.1
TNFRSF1A	NM_001346092.2 linkuse as main transcript	c.281-9T>C	splice_polypyrimidine_tract_variant, intron_variant		NP_001333021.1
TNFRSF1A	NR_144351.2 linkuse as main transcript	n.928-9T>C	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 linkuse as main transcript	c.740-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001065.4	ENSP00000162749	P1	P19438-1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38810

AN:

151976

Hom.:

5227

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.240

AC XY:

174134

AN XY:

726140

show subpopulations

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.:

AF XY:

0.261

AC XY:

19389

AN XY:

74328

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over