chr17-7549176-G-A

Position:

• chr17-7549176-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003809.3(TNFSF12):​c.23G>A​(p.Arg8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,299,594 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: TNFSF12 NM_003809.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22773424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF12	NM_003809.3	c.23G>A	p.Arg8Lys	missense_variant	1/7	ENST00000293825.11
TNFSF12-TNFSF13	NM_172089.4	c.23G>A	p.Arg8Lys	missense_variant	1/11
TNFSF12	NR_037146.2	n.119G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF12	ENST00000293825.11	c.23G>A	p.Arg8Lys	missense_variant	1/7	1	NM_003809.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.72e-7 AC: 1 AN: 1147374 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 550612

Gnomad4 AFR exome AF: 0.0000431

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74420

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Common variable immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

This sequence change replaces arginine with lysine at codon 8 of the TNFSF12 protein (p.Arg8Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. 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 variant has not been reported in the literature in individuals affected with TNFSF12-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.54	N;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.13	B;.
Vest4		0.16
MutPred		0.15		Gain of glycosylation at R8 (P = 0.059);Gain of glycosylation at R8 (P = 0.059);
MVP		0.37
MPC		0.44
ClinPred		0.72	D
GERP RS		4.1
Varity_R		0.27
gMVP		0.23

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: rs958789070; hg19: chr17-7452493;