chr17-7549491-G-T

Position:

• chr17-7549491-G-T

Variant summary

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

The NM_003809.3(TNFSF12):​c.177G>T​(p.Glu59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFSF12 NM_003809.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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: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 (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=0.08740911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFSF12	NM_003809.3	c.177G>T	p.Glu59Asp	missense_variant	2/7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4	c.177G>T	p.Glu59Asp	missense_variant	2/11		NP_742086.1
TNFSF12	NR_037146.2	n.273G>T		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11	c.177G>T	p.Glu59Asp	missense_variant	2/7	1	NM_003809.3	ENSP00000293825.6
TNFSF12-TNFSF13	ENST00000293826.4	c.177G>T	p.Glu59Asp	missense_variant	2/11	1		ENSP00000293826.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395820 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0020	B;.
Vest4		0.12
MutPred		0.11		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.19
MPC		0.41
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs868687352; hg19: chr17-7452808;