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GeneBe

rs35160621

chr1-1211585-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_003327.4(TNFRSF4):c.804C>T(p.Ala268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,519,314 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 33)
Exomes 𝑓: 0.00049 ( 6 hom. )

Consequence

TNFRSF4
NM_003327.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -11.3
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-1.02).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-1211585-G-A is Benign according to our data. Variant chr1-1211585-G-A is described in ClinVar as [Benign]. Clinvar id is 474798.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1211585-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-11.3 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (797/152180) while in subpopulation AFR AF= 0.0183 (761/41536). AF 95% confidence interval is 0.0172. There are 6 homozygotes in gnomad4. There are 376 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNFRSF4NM_003327.4 linkuse as main transcriptc.804C>T p.Ala268= synonymous_variant 7/7 ENST00000379236.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFRSF4ENST00000379236.4 linkuse as main transcriptc.804C>T p.Ala268= synonymous_variant 7/71 NM_003327.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00525
AC:
798
AN:
152062
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0184
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.00158
AC:
274
AN:
173932
Hom.:
5
AF XY:
0.00105
AC XY:
98
AN XY:
93580
show subpopulations
Gnomad AFR exome
AF:
0.0177
Gnomad AMR exome
AF:
0.000706
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000177
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000122
Gnomad OTH exome
AF:
0.000762
GnomAD4 exome
AF:
0.000489
AC:
668
AN:
1367134
Hom.:
6
Cov.:
30
AF XY:
0.000401
AC XY:
269
AN XY:
671524
show subpopulations
Gnomad4 AFR exome
AF:
0.0172
Gnomad4 AMR exome
AF:
0.000879
Gnomad4 ASJ exome
AF:
0.0000490
Gnomad4 EAS exome
AF:
0.0000272
Gnomad4 SAS exome
AF:
0.000138
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000637
Gnomad4 OTH exome
AF:
0.00102
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00524
AC:
797
AN:
152180
Hom.:
6
Cov.:
33
AF XY:
0.00505
AC XY:
376
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.0183
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.00403
Hom.:
0
Bravo
AF:
0.00598
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Combined immunodeficiency due to OX40 deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-1.0
Cadd
Benign
0.049
Dann
Benign
0.59

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.

Other links and lift over

dbSNP: rs35160621; hg19: chr1-1146965; COSMIC: COSV64878794; COSMIC: COSV64878794; API