17-7549196-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.73

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-TNFSF13 (HGNC:):

ACMG classification

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	UniProt
TNFSF12	NM_003809.3	c.43G>A	p.Glu15Lys	missense_variant	1/7	ENST00000293825.11
TNFSF12-TNFSF13	NM_172089.4	c.43G>A	p.Glu15Lys	missense_variant	1/11
TNFSF12	NR_037146.2	n.139G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF12	ENST00000293825.11	c.43G>A	p.Glu15Lys	missense_variant	1/7	1	NM_003809.3	P4

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151928 Hom.: 0 Cov.: 32

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: 2 AN: 3454 Hom.: 0 AF XY: 0.000449 AC XY: 1 AN XY: 2226

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.: 0 Cov.: 31 AF XY: 0.000404 AC XY: 225 AN XY: 557608

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: 61 AN: 151928 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74218

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.: 0

Bravo AF: 0.000635

ExAC AF: 0.000441 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 09, 2020

- -

Common variable immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0040	T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.65	N;N;N
PrimateAI	Pathogenic	0.82	D
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	T
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

Other links and lift over

dbSNP: rs768061768; hg19: chr17-7452513;