Variant 17-7549241-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003809.3(TNFSF12):c.88C>G(p.Leu30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000808 in 1,237,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

TNFSF12
NM_003809.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91

Variant links:

Genes affected

TNFSF12 (HGNC:11927): (TNF superfamily member 12) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. This cytokine, which exists in both membrane-bound and secreted forms, can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis. Alternative splicing results in multiple transcript variants. Some transcripts skip the last exon of this gene and continue into the second exon of the neighboring TNFSF13 gene; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13. [provided by RefSeq, Oct 2010]

TNFSF12 links:

TNFSF12-TNFSF13 (HGNC:):

TNFSF12-TNFSF13 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFSF12	NM_003809.3 linkuse as main transcript	c.88C>G	p.Leu30Val	missense_variant	1/7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4 linkuse as main transcript	c.88C>G	p.Leu30Val	missense_variant	1/11		NP_742086.1
TNFSF12	NR_037146.2 linkuse as main transcript	n.184C>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11 linkuse as main transcript	c.88C>G	p.Leu30Val	missense_variant	1/7	1	NM_003809.3	ENSP00000293825	P4	O43508-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.08e-7

AC:

AN:

1237950

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

603964

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:

9.92e-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

Common variable immunodeficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2021

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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TNFSF12-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces leucine with valine at codon 30 of the TNFSF12 protein (p.Leu30Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.78

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

0.65

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.15

N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.50

T;T

Polyphen

0.99

D;.

Vest4

0.29

MutPred

0.25

Gain of catalytic residue at L30 (P = 0.0492);Gain of catalytic residue at L30 (P = 0.0492);

MVP

0.72

MPC

0.43

ClinPred

0.80

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

gMVP

0.24

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

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