17-7549196-G-A

Position:

chr17-7549196-G-A

Variant summary

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

The NM_003809.3(TNFSF12):c.43G>A(p.Glu15Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000378 in 1,310,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

TNFSF12
NM_003809.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.73

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:

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=0.004021287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFSF12	NM_003809.3 linkuse as main transcript	c.43G>A	p.Glu15Lys	missense_variant	1/7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4 linkuse as main transcript	c.43G>A	p.Glu15Lys	missense_variant	1/11		NP_742086.1
TNFSF12	NR_037146.2 linkuse as main transcript	n.139G>A		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.43G>A	p.Glu15Lys	missense_variant	1/7	1	NM_003809.3	ENSP00000293825	P4	O43508-1

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000579

AC:

AN:

3454

Hom.:

AF XY:

0.000449

AC XY:

AN XY:

2226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00935

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000375

AC:

434

AN:

1158762

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

225

AN XY:

557608

show subpopulations

Gnomad4 AFR exome

AF:

0.000342

Gnomad4 AMR exome

AF:

0.000991

Gnomad4 ASJ exome

AF:

0.00716

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000255

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000402

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000624

Hom.:

Bravo

AF:

0.000635

ExAC

AF:

0.000441

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 09, 2020

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Common variable immunodeficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 15 of the TNFSF12 protein (p.Glu15Lys). This variant is present in population databases (rs768061768, gnomAD 0.6%). This variant has not been reported in the literature in individuals affected with TNFSF12-related conditions. ClinVar contains an entry for this variant (Variation ID: 526011). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

0.21

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0040

T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

0.65

N;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.21

T;T

Polyphen

0.32

B;.

Vest4

0.24

MutPred

0.24

Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);

MVP

0.15

MPC

0.49

ClinPred

0.26

GERP RS

4.1

Varity_R

0.33

gMVP

0.22

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over