17-7549213-G-T

Variant names:

• chr17-7549213-G-T
• rs898490512
• NM_003809.3:c.60G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_003809.3(TNFSF12):​c.60G>T​(p.Leu20Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000836 in 1,196,256 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: TNFSF12 NM_003809.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-7549213-G-T is Benign according to our data. Variant chr17-7549213-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1086838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF12	NM_003809.3	MANE Select	c.60G>T	p.Leu20Leu	synonymous	Exon 1 of 7	NP_003800.1	O43508-1
	TNFSF12-TNFSF13	NM_172089.4		c.60G>T	p.Leu20Leu	synonymous	Exon 1 of 11	NP_742086.1	A0A0A6YY99
	TNFSF12	NR_037146.2		n.156G>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF12	ENST00000293825.11	TSL:1 MANE Select	c.60G>T	p.Leu20Leu	synonymous	Exon 1 of 7	ENSP00000293825.6	O43508-1
	TNFSF12-TNFSF13	ENST00000293826.4	TSL:1	c.60G>T	p.Leu20Leu	synonymous	Exon 1 of 11	ENSP00000293826.4
	TNFSF12	ENST00000322272.11	TSL:1	n.60G>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000314636.7	C0H5Y4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1196256 Hom.: 0 Cov.: 31 AF XY: 0.00000172 AC XY: 1 AN XY: 580098

African (AFR) AF: 0.00 AC: 0 AN: 23882

American (AMR) AF: 0.00 AC: 0 AN: 11334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16902

East Asian (EAS) AF: 0.00 AC: 0 AN: 27376

South Asian (SAS) AF: 0.00 AC: 0 AN: 49640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 986300

Other (OTH) AF: 0.0000204 AC: 1 AN: 48930

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Common variable immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		1.2
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs898490512; hg19: chr17-7452530;