rs151344628

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001065.4(TNFRSF1A):​c.1075C>T​(p.Leu359Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,593,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

TNFRSF1A
NM_001065.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 2.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 12-6329605-G-A is Benign according to our data. Variant chr12-6329605-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 97422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6329605-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=2.99 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000499 (76/152308) while in subpopulation AMR AF= 0.00124 (19/15306). AF 95% confidence interval is 0.000812. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNFRSF1ANM_001065.4 linkc.1075C>T p.Leu359Leu synonymous_variant Exon 10 of 10 ENST00000162749.7 NP_001056.1 P19438-1
TNFRSF1ANM_001346091.2 linkc.751C>T p.Leu251Leu synonymous_variant Exon 9 of 9 NP_001333020.1 P19438-2J9PH39
TNFRSF1ANM_001346092.2 linkc.616C>T p.Leu206Leu synonymous_variant Exon 11 of 11 NP_001333021.1 P19438
TNFRSF1ANR_144351.2 linkn.1263C>T non_coding_transcript_exon_variant Exon 9 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFRSF1AENST00000162749.7 linkc.1075C>T p.Leu359Leu synonymous_variant Exon 10 of 10 1 NM_001065.4 ENSP00000162749.2 P19438-1

Frequencies

GnomAD3 genomes
AF:
0.000499
AC:
76
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
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:
0.000706
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000572
AC:
127
AN:
222140
Hom.:
0
AF XY:
0.000454
AC XY:
56
AN XY:
123276
show subpopulations
Gnomad AFR exome
AF:
0.000144
Gnomad AMR exome
AF:
0.00169
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000805
Gnomad NFE exome
AF:
0.000599
Gnomad OTH exome
AF:
0.00125
GnomAD4 exome
AF:
0.000647
AC:
933
AN:
1440942
Hom.:
0
Cov.:
32
AF XY:
0.000626
AC XY:
448
AN XY:
716146
show subpopulations
Gnomad4 AFR exome
AF:
0.0000604
Gnomad4 AMR exome
AF:
0.00170
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000246
Gnomad4 NFE exome
AF:
0.000739
Gnomad4 OTH exome
AF:
0.000619
GnomAD4 genome
AF:
0.000499
AC:
76
AN:
152308
Hom.:
0
Cov.:
33
AF XY:
0.000550
AC XY:
41
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000706
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000385
Hom.:
0
Bravo
AF:
0.000714

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

TNF receptor-associated periodic fever syndrome (TRAPS) Benign:1Other:1
-
Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Apr 24, 2012
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autoinflammatory syndrome Benign:1
Apr 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
CADD
Benign
5.7
DANN
Benign
0.95
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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.

Other links and lift over

dbSNP: rs151344628; hg19: chr12-6438771; API