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GeneBe

1-7933162-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001561.6(TNFRSF9):c.679C>T(p.Pro227Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000622 in 1,606,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

TNFRSF9
NM_001561.6 missense, splice_region

Scores

3
8
Splicing: ADA: 0.9855
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71
Variant links:
Genes affected
TNFRSF9 (HGNC:11924): (TNF receptor superfamily member 9) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
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 (MetaRNN=0.033348233).
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000646 (94/1454440) while in subpopulation SAS AF= 0.000613 (52/84808). AF 95% confidence interval is 0.00048. There are 0 homozygotes in gnomad4_exome. There are 62 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNFRSF9NM_001561.6 linkuse as main transcriptc.679C>T p.Pro227Ser missense_variant, splice_region_variant 7/8 ENST00000377507.8
TNFRSF9XM_006710618.4 linkuse as main transcriptc.679C>T p.His227Tyr missense_variant, splice_region_variant 7/8
TNFRSF9XM_047419672.1 linkuse as main transcriptc.679C>T p.Gln227Ter stop_gained, splice_region_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFRSF9ENST00000377507.8 linkuse as main transcriptc.679C>T p.Pro227Ser missense_variant, splice_region_variant 7/81 NM_001561.6 P1
TNFRSF9ENST00000474475.1 linkuse as main transcriptc.223C>T p.His75Tyr missense_variant, splice_region_variant 2/33
TNFRSF9ENST00000492571.1 linkuse as main transcriptc.*321C>T 3_prime_UTR_variant, NMD_transcript_variant 5/53

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000395
AC:
6
AN:
152054
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000769
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000150
AC:
37
AN:
245962
Hom.:
0
AF XY:
0.000203
AC XY:
27
AN XY:
132954
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000152
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000441
Gnomad SAS exome
AF:
0.000616
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000446
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000646
AC:
94
AN:
1454440
Hom.:
0
Cov.:
30
AF XY:
0.0000858
AC XY:
62
AN XY:
722958
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000116
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000304
Gnomad4 SAS exome
AF:
0.000613
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000394
AC:
6
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000340
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000181
AC:
22
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 08, 2022This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the TNFRSF9 protein (p.Pro227Ser). This variant is present in population databases (rs533883433, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with TNFRSF9-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.27
Cadd
Uncertain
26
Dann
Uncertain
1.0
Eigen
Benign
0.18
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.25
T
M_CAP
Uncertain
0.094
D
MetaRNN
Benign
0.033
T
MutationTaster
Benign
1.0
D
MVP
0.36
ClinPred
0.083
T
GERP RS
3.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Benign
0.60
SpliceAI score (max)
0.080
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: rs533883433; hg19: chr1-7993222; COSMIC: COSV66348896; API