chr12-6330304-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001065.4(TNFRSF1A):c.740-9T>C variant causes a 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 intron

Scores

Splicing: ADA: 0.00009474

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.13

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

TNF receptor 1-associated periodic fever syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Illumina, Laboratory for Molecular Medicine, Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P

TNFRSF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 257327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001065.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNFRSF1A	NM_001065.4	MANE Select	c.740-9T>C	intron	N/A	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2		c.416-9T>C	intron	N/A	NP_001333020.1	P19438-2
TNFRSF1A	NM_001346092.2		c.281-9T>C	intron	N/A	NP_001333021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.740-9T>C	intron	N/A	ENSP00000162749.2	P19438-1
TNFRSF1A	ENST00000540022.5	TSL:1	c.611-9T>C	intron	N/A	ENSP00000438343.1	F5H061
TNFRSF1A	ENST00000366159.9	TSL:1	n.1841-9T>C	intron	N/A

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

GnomAD2 exomes

AF:

0.280

AC:

70416

AN:

251338

AF XY:

0.283

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 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

African (AFR)

AF:

0.272

AC:

9080

AN:

33428

American (AMR)

AF:

0.389

AC:

17412

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

6831

AN:

26108

East Asian (EAS)

AF:

0.359

AC:

14239

AN:

39686

South Asian (SAS)

AF:

0.437

AC:

37673

AN:

86190

European-Finnish (FIN)

AF:

0.229

AC:

12208

AN:

53342

Middle Eastern (MID)

AF:

0.288

AC:

1660

AN:

5762

European-Non Finnish (NFE)

AF:

0.205

AC:

228016

AN:

1109842

Other (OTH)

AF:

0.252

AC:

15200

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13685

27370

41054

54739

68424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8268

16536

24804

33072

41340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.255

AC:

38854

AN:

152094

Hom.:

5239

Cov.:

AF XY:

0.261

AC XY:

19389

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.274

AC:

11364

AN:

41466

American (AMR)

AF:

0.343

AC:

5239

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

859

AN:

3468

East Asian (EAS)

AF:

0.337

AC:

1739

AN:

5160

South Asian (SAS)

AF:

0.444

AC:

2138

AN:

4816

European-Finnish (FIN)

AF:

0.219

AC:

2323

AN:

10588

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14248

AN:

67986

Other (OTH)

AF:

0.287

AC:

606

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1486

2972

4457

5943

7429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.228

Hom.:

3710

Bravo

AF:

0.262

Asia WGS

AF:

0.390

AC:

1358

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over