Variant 19-6665350-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001376887.1(TNFSF14):c.299G>A(p.Gly100Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TNFSF14
NM_001376887.1 missense, splice_region

Scores

Splicing: ADA: 0.9953

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14

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]

TNFSF14 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFSF14	NM_001376887.1 linkuse as main transcript	c.299G>A	p.Gly100Glu	missense_variant, splice_region_variant	4/4	ENST00000675206.1	NP_001363816.1
TNFSF14	NM_003807.5 linkuse as main transcript	c.299G>A	p.Gly100Glu	missense_variant, splice_region_variant	5/5		NP_003798.2
TNFSF14	NM_172014.3 linkuse as main transcript	c.191G>A	p.Gly64Glu	missense_variant, splice_region_variant	4/4		NP_742011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF14	ENST00000675206.1 linkuse as main transcript	c.299G>A	p.Gly100Glu	missense_variant, splice_region_variant	4/4		NM_001376887.1	ENSP00000502837	P1	O43557-1
TNFSF14	ENST00000599359.1 linkuse as main transcript	c.299G>A	p.Gly100Glu	missense_variant, splice_region_variant	5/5	1		ENSP00000469049	P1	O43557-1
TNFSF14	ENST00000245912.7 linkuse as main transcript	c.191G>A	p.Gly64Glu	missense_variant, splice_region_variant	4/4	1		ENSP00000245912		O43557-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410928

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.19e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.299G>A (p.G100E) 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 299, causing the glycine (G) at amino acid position 100 to be replaced by a glutamic acid (E). 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

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

0.94

D;D

PrimateAI

Uncertain

0.66

REVEL

Benign

0.23

Sift4G

Uncertain

0.021

D;T

Polyphen

1.0

D;D

Vest4

0.81

MutPred

0.39

.;Gain of disorder (P = 0.0894);

MVP

0.97

MPC

1.2

ClinPred

0.96

GERP RS

4.9

Varity_R

0.76

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over