rs768061768

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Publications

0 publications found

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:33537): (TNFSF12-TNFSF13 readthrough) This gene encodes a member of the tumor necrosis factor superfamily. It encodes a hybrid protein composed of the cytoplasmic and transmembrane domains of family member 12 fused to the C-terminal domain of family member 13. The hybrid protein is membrane anchored and presents the receptor-binding domain of family member 13 at the cell surface. It stimulates cycling in T- and B-lymphoma cell lines. [provided by RefSeq, Jul 2008]

TNFSF12-TNFSF13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004021287).

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNFSF12	NM_003809.3 link	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4 link	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 11		NP_742086.1
TNFSF12	NR_037146.2 link	n.139G>A		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11 link	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 7	1	NM_003809.3	ENSP00000293825.6
TNFSF12-TNFSF13	ENST00000293826.4 link	c.43G>A	p.Glu15Lys	missense_variant	Exon 1 of 11	1		ENSP00000293826.4

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

GnomAD2 exomes

AF:

0.000579

AC:

AN:

3454

AF XY:

0.000449

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 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

African (AFR)

AF:

0.000342

AC:

AN:

23382

American (AMR)

AF:

0.000991

AC:

AN:

9086

Ashkenazi Jewish (ASJ)

AF:

0.00716

AC:

113

AN:

15772

East Asian (EAS)

AF:

0.00

AC:

AN:

26972

South Asian (SAS)

AF:

0.00

AC:

AN:

40654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26590

Middle Eastern (MID)

AF:

0.00251

AC:

AN:

3182

European-Non Finnish (NFE)

AF:

0.000255

AC:

246

AN:

965904

Other (OTH)

AF:

0.00106

AC:

AN:

47220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000402

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41384

American (AMR)

AF:

0.000590

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67934

Other (OTH)

AF:

0.00191

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jul 09, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Common variable immunodeficiency

Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

3.7

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

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.33

gMVP

0.22

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over