chr12-6333405-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_001065.4(TNFRSF1A):c.434A>G(p.Asn145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

TNFRSF1A
NM_001065.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: 2.55

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a strand (size 5) in uniprot entity TNR1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001065.4

BP4

Computational evidence support a benign effect (MetaRNN=0.37801474).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000978 (143/1461720) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.0000912. There are 0 homozygotes in GnomAdExome4. There are 74 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4 link	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 10	ENST00000162749.7	NP_001056.1	P19438-1
TNFRSF1A	NM_001346091.2 link	c.110A>G	p.Asn37Ser	missense_variant	Exon 3 of 9		NP_001333020.1	P19438-2J9PH39
TNFRSF1A	NM_001346092.2 link	c.-144A>G		5_prime_UTR_variant	Exon 4 of 11		NP_001333021.1	P19438
TNFRSF1A	NR_144351.2 link	n.696A>G		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7 link	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 10	1	NM_001065.4	ENSP00000162749.2		P19438-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000918

AC:

AN:

250598

AF XY:

0.0000886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000978

AC:

143

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000179

AC:

AN:

44684

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26126

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86208

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53398

Gnomad4 NFE exome

AF:

0.000107

AC:

119

AN:

1111960

Gnomad4 Remaining exome

AF:

0.0000828

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000103

AC:

0.000102896

AN:

0.000102896

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000170

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS)

Uncertain:1Benign:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2

Mar 08, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N145S variant has been published in association with TRAPS (Lachmann et al., 2014). The N145S variant was not observed at any significant frequency in individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The N145S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Febrile seizure (within the age range of 3 months to 6 years);C0019214:Hepatosplenomegaly

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Uncertain:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.61

D;T;T;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.85

D;T;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.7

L;.;.;L;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.017

D;D;T;T;T

Sift4G

Uncertain

0.059

T;T;.;T;.

Polyphen

0.85

P;P;.;.;.

Vest4

0.36

MVP

0.81

MPC

0.58

ClinPred

0.12

GERP RS

0.93

Varity_R

0.33

gMVP

0.94

Mutation Taster

=71/29

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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