NM_003809.3:c.23G>A

Variant names:

• chr17-7549176-G-A
• rs958789070
• NM_003809.3:c.23G>A

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.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
• 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=0.22773424).

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.23G>A	p.Arg8Lys	missense	Exon 1 of 7	NP_003800.1	O43508-1
	TNFSF12-TNFSF13	NM_172089.4		c.23G>A	p.Arg8Lys	missense	Exon 1 of 11	NP_742086.1	A0A0A6YY99
	TNFSF12	NR_037146.2		n.119G>A		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.23G>A	p.Arg8Lys	missense	Exon 1 of 7	ENSP00000293825.6	O43508-1
	TNFSF12-TNFSF13	ENST00000293826.4	TSL:1	c.23G>A	p.Arg8Lys	missense	Exon 1 of 11	ENSP00000293826.4
	TNFSF12	ENST00000322272.11	TSL:1	n.23G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000314636.7	C0H5Y4

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

African (AFR) AF: 0.0000431 AC: 1 AN: 23182

American (AMR) AF: 0.00 AC: 0 AN: 8666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15432

East Asian (EAS) AF: 0.00 AC: 0 AN: 26814

South Asian (SAS) AF: 0.00 AC: 0 AN: 38004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 959508

Other (OTH) AF: 0.00 AC: 0 AN: 46710

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

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
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
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.13	B
Vest4		0.16
MutPred		0.15		Gain of glycosylation at R8 (P = 0.059)
MVP		0.37
MPC		0.44
ClinPred		0.72	D
GERP RS		4.1
PromoterAI		-0.095	Neutral
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

Other links and lift over

dbSNP: rs958789070; hg19: chr17-7452493;