19-6665330-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001376887.1(TNFSF14):​c.319G>A​(p.Gly107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,589,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TNFSF14
NM_001376887.1 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.306
Variant links:
Genes affected
TNFSF14 (HGNC:11930): (TNF superfamily member 14) The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF14, which is a member of the tumor necrosis factor receptor superfamily, and which is also known as a herpesvirus entry mediator (HVEM). This protein may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus. This protein has been shown to stimulate the proliferation of T cells, and trigger apoptosis of various tumor cells. This protein is also reported to prevent tumor necrosis factor alpha mediated apoptosis in primary hepatocyte. Two alternatively spliced transcript variant encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.039141446).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNFSF14NM_001376887.1 linkuse as main transcriptc.319G>A p.Gly107Ser missense_variant 4/4 ENST00000675206.1 NP_001363816.1
TNFSF14NM_003807.5 linkuse as main transcriptc.319G>A p.Gly107Ser missense_variant 5/5 NP_003798.2
TNFSF14NM_172014.3 linkuse as main transcriptc.211G>A p.Gly71Ser missense_variant 4/4 NP_742011.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNFSF14ENST00000675206.1 linkuse as main transcriptc.319G>A p.Gly107Ser missense_variant 4/4 NM_001376887.1 ENSP00000502837 P1O43557-1
TNFSF14ENST00000599359.1 linkuse as main transcriptc.319G>A p.Gly107Ser missense_variant 5/51 ENSP00000469049 P1O43557-1
TNFSF14ENST00000245912.7 linkuse as main transcriptc.211G>A p.Gly71Ser missense_variant 4/41 ENSP00000245912 O43557-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152244
Hom.:
0
Cov.:
32
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000196
AC:
4
AN:
203826
Hom.:
0
AF XY:
0.0000267
AC XY:
3
AN XY:
112230
show subpopulations
Gnomad AFR exome
AF:
0.0000802
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000111
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000216
AC:
31
AN:
1437476
Hom.:
0
Cov.:
36
AF XY:
0.0000238
AC XY:
17
AN XY:
713338
show subpopulations
Gnomad4 AFR exome
AF:
0.0000302
Gnomad4 AMR exome
AF:
0.0000486
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000358
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000227
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152362
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000252
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 31, 2022The c.319G>A (p.G107S) alteration is located in exon 5 (coding exon 4) of the TNFSF14 gene. This alteration results from a G to A substitution at nucleotide position 319, causing the glycine (G) at amino acid position 107 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
5.5
DANN
Benign
0.50
DEOGEN2
Benign
0.17
.;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.0058
N
LIST_S2
Benign
0.61
T;T
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.039
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.81
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.36
T
REVEL
Benign
0.012
Sift4G
Benign
0.54
T;T
Polyphen
0.010
B;B
Vest4
0.080
MVP
0.24
MPC
0.33
ClinPred
0.014
T
GERP RS
-3.3
Varity_R
0.092
gMVP
0.46

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: rs553799062; hg19: chr19-6665341; API