17-7549196-G-C

Variant names:

• chr17-7549196-G-C
• rs768061768
• NM_003809.3:c.43G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003809.3(TNFSF12):​c.43G>C​(p.Glu15Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000863 in 1,158,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E15K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: TNFSF12 NM_003809.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22094128).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003809.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF12	NM_003809.3	MANE Select	c.43G>C	p.Glu15Gln	missense	Exon 1 of 7	NP_003800.1
	TNFSF12-TNFSF13	NM_172089.4		c.43G>C	p.Glu15Gln	missense	Exon 1 of 11	NP_742086.1
	TNFSF12	NR_037146.2		n.139G>C		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF12	ENST00000293825.11	TSL:1 MANE Select	c.43G>C	p.Glu15Gln	missense	Exon 1 of 7	ENSP00000293825.6
	TNFSF12-TNFSF13	ENST00000293826.4	TSL:1	c.43G>C	p.Glu15Gln	missense	Exon 1 of 11	ENSP00000293826.4
	TNFSF12	ENST00000322272.11	TSL:1	n.43G>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000314636.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.63e-7 AC: 1 AN: 1158762 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 557608

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23382

American (AMR) AF: 0.00 AC: 0 AN: 9086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15772

East Asian (EAS) AF: 0.00 AC: 0 AN: 26972

South Asian (SAS) AF: 0.0000246 AC: 1 AN: 40654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3182

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965904

Other (OTH) AF: 0.00 AC: 0 AN: 47220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.059
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.13	T
Polyphen		0.49	P
Vest4		0.10
MutPred		0.10		Gain of MoRF binding (P = 0.0365)
MVP		0.33
MPC		0.43
ClinPred		0.84	D
GERP RS		4.1
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.20

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

Other links and lift over

dbSNP: rs768061768; hg19: chr17-7452513;