NM_001065.4:c.473-33T>C

Variant names:

Variant summary

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

The NM_001065.4(TNFRSF1A):c.473-33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,608,846 control chromosomes in the GnomAD database, including 314,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 39057 hom., cov: 32)

Exomes 𝑓: 0.61 ( 275738 hom. )

Consequence

TNFRSF1A
NM_001065.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.364

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 (MetaRNN=9.108376E-7).

BP6

Variant 12-6333180-A-G is Benign according to our data. Variant chr12-6333180-A-G is described in ClinVar as [Benign]. Clinvar id is 1166190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6333180-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.473-33T>C	intron_variant	Intron 4 of 9	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2 link	c.149-33T>C	intron_variant	Intron 3 of 8		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.-105-33T>C	intron_variant	Intron 4 of 10		NP_001333021.1	P19438
TNFRSF1A	NR_144351.2 link	n.735-33T>C	intron_variant	Intron 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.473-33T>C		intron_variant	Intron 4 of 9	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.702

AC:

106731

AN:

151986

Hom.:

39001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.914

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.674

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.687

Gnomad FIN

AF:

0.626

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.602

Gnomad OTH

AF:

0.694

GnomAD3 exomes

AF:

0.644

AC:

159487

AN:

247490

Hom.:

52512

AF XY:

0.638

AC XY:

85322

AN XY:

133804

show subpopulations

Gnomad AFR exome

AF:

0.919

Gnomad AMR exome

AF:

0.728

Gnomad ASJ exome

AF:

0.673

Gnomad EAS exome

AF:

0.472

Gnomad SAS exome

AF:

0.689

Gnomad FIN exome

AF:

0.621

Gnomad NFE exome

AF:

0.597

Gnomad OTH exome

AF:

0.644

GnomAD4 exome

AF:

0.611

AC:

890648

AN:

1456742

Hom.:

275738

Cov.:

AF XY:

0.613

AC XY:

444273

AN XY:

724756

show subpopulations

Gnomad4 AFR exome

AF:

0.926

Gnomad4 AMR exome

AF:

0.726

Gnomad4 ASJ exome

AF:

0.675

Gnomad4 EAS exome

AF:

0.540

Gnomad4 SAS exome

AF:

0.684

Gnomad4 FIN exome

AF:

0.625

Gnomad4 NFE exome

AF:

0.591

Gnomad4 OTH exome

AF:

0.625

GnomAD4 genome

AF:

0.702

AC:

106847

AN:

152104

Hom.:

39057

Cov.:

AF XY:

0.704

AC XY:

52321

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.914

Gnomad4 AMR

AF:

0.723

Gnomad4 ASJ

AF:

0.674

Gnomad4 EAS

AF:

0.483

Gnomad4 SAS

AF:

0.687

Gnomad4 FIN

AF:

0.626

Gnomad4 NFE

AF:

0.602

Gnomad4 OTH

AF:

0.695

Alfa

AF:

0.665

Hom.:

10108

Bravo

AF:

0.713

TwinsUK

AF:

0.602

AC:

2233

ALSPAC

AF:

0.582

AC:

2244

ESP6500AA

AF:

0.901

AC:

3969

ESP6500EA

AF:

0.598

AC:

5140

ExAC

AF:

0.641

AC:

77847

Asia WGS

AF:

0.635

AC:

2209

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23505244) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

TNF receptor-associated periodic fever syndrome (TRAPS)

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

0.25

DANN

Benign

0.66

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.16

MetaRNN

Benign

9.1e-7

MetaSVM

Benign

-0.96

PROVEAN

Benign

1.1

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

ClinPred

0.040

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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