Genetic Variant NM_001065.4:c.224C>T (chr12-6333835-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_001065.4(TNFRSF1A):c.224C>T(p.Pro75Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,599,400 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 139 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 133 hom. )

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.72

Publications

33 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001065.4

BP4

Computational evidence support a benign effect (MetaRNN=0.00295794).

BP6

Variant 12-6333835-G-A is Benign according to our data. Variant chr12-6333835-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245671.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF1A	NM_001065.4	MANE Select	c.224C>T	p.Pro75Leu	missense	Exon 3 of 10	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2		c.-101C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001333020.1	P19438-2
TNFRSF1A	NM_001346092.2		c.-354C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001333021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.224C>T	p.Pro75Leu	missense	Exon 3 of 10	ENSP00000162749.2	P19438-1
TNFRSF1A	ENST00000540022.5	TSL:1	c.193+256C>T		intron	N/A	ENSP00000438343.1	F5H061
TNFRSF1A	ENST00000366159.9	TSL:1	n.258C>T		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3500

AN:

152142

Hom.:

138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0782

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00574

AC:

1290

AN:

224860

AF XY:

0.00421

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.00414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000399

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00274

AC:

3962

AN:

1447140

Hom.:

133

Cov.:

AF XY:

0.00241

AC XY:

1735

AN XY:

718564

show subpopulations

African (AFR)

AF:

0.0861

AC:

2861

AN:

33232

American (AMR)

AF:

0.00546

AC:

231

AN:

42292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25748

East Asian (EAS)

AF:

0.00

AC:

AN:

39110

South Asian (SAS)

AF:

0.000178

AC:

AN:

84270

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52396

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000414

AC:

457

AN:

1104444

Other (OTH)

AF:

0.00626

AC:

375

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

243

485

728

970

1213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.0231

AC:

3513

AN:

152260

Hom.:

139

Cov.:

AF XY:

0.0214

AC XY:

1596

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0783

AC:

3255

AN:

41556

American (AMR)

AF:

0.0125

AC:

192

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68020

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

166

331

497

662

828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00787

Hom.:

104

Bravo

AF:

0.0272

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0738

AC:

325

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00656

AC:

796

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

TNF receptor-associated periodic fever syndrome (TRAPS) (3)

Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.085

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.5

PhyloP100

1.7

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.38

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.47

MVP

0.89

MPC

0.79

ClinPred

0.063

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.96

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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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