rs35304565

Positions:

chr1-1214100-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003327.4(TNFRSF4):c.28C>T(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,585,918 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0080 ( 95 hom. )

Consequence

TNFRSF4
NM_003327.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.340

Variant links:

Genes affected

TNFRSF4 (HGNC:11918): (TNF receptor superfamily member 4) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

TNFRSF4 links:

TNFRSF4 (HGNC:):

TNFRSF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057964325).

BP6

Variant 1-1214100-G-A is Benign according to our data. Variant chr1-1214100-G-A is described in ClinVar as [Benign]. Clinvar id is 474794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00527 (803/152330) while in subpopulation SAS AF= 0.0193 (93/4822). AF 95% confidence interval is 0.0161. There are 5 homozygotes in gnomad4. There are 388 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF4	NM_003327.4 linkuse as main transcript	c.28C>T	p.Arg10Cys	missense_variant	1/7	ENST00000379236.4	NP_003318.1	P43489
TNFRSF4	NM_001410709.1 linkuse as main transcript	c.28C>T	p.Arg10Cys	missense_variant	1/6		NP_001397638.1
TNFRSF4	XR_007063145.1 linkuse as main transcript	n.54C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF4	ENST00000379236.4 linkuse as main transcript	c.28C>T	p.Arg10Cys	missense_variant	1/7	1	NM_003327.4	ENSP00000368538.3		P43489

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00679

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00854

AC:

1757

AN:

205672

Hom.:

AF XY:

0.00985

AC XY:

1115

AN XY:

113210

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00352

Gnomad ASJ exome

AF:

0.00848

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0255

Gnomad FIN exome

AF:

0.00511

Gnomad NFE exome

AF:

0.00796

Gnomad OTH exome

AF:

0.00841

GnomAD4 exome

AF:

0.00799

AC:

11452

AN:

1433588

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

6023

AN XY:

711812

show subpopulations

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.00335

Gnomad4 ASJ exome

AF:

0.00929

Gnomad4 EAS exome

AF:

0.0000514

Gnomad4 SAS exome

AF:

0.0244

Gnomad4 FIN exome

AF:

0.00580

Gnomad4 NFE exome

AF:

0.00736

Gnomad4 OTH exome

AF:

0.00881

GnomAD4 genome

AF:

0.00527

AC:

803

AN:

152330

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

388

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00562

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.00678

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00712

Hom.:

Bravo

AF:

0.00500

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.00736

AC:

ExAC

AF:

0.00785

AC:

932

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to OX40 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

TNFRSF4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.12

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.011

Polyphen

0.98

Vest4

0.16

MVP

0.62

MPC

0.20

ClinPred

0.016

GERP RS

2.2

Varity_R

0.17

gMVP

0.84

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