chr17-7555265-A-T

Variant names:

• chr17-7555265-A-T
• rs12937543
• NM_003809.3:c.374-1513A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003809.3(TNFSF12):​c.374-1513A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 151,912 control chromosomes in the GnomAD database, including 15,302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (15302 hom., cov: 31)
• Consequence: TNFSF12 NM_003809.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF12	NM_003809.3	c.374-1513A>T		intron_variant	Intron 5 of 6	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4	c.374-1513A>T		intron_variant	Intron 5 of 10		NP_742086.1
TNFSF12	NR_037146.2	n.708+1440A>T		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11	c.374-1513A>T		intron_variant	Intron 5 of 6	1	NM_003809.3	ENSP00000293825.6
TNFSF12-TNFSF13	ENST00000293826.4	c.374-1513A>T		intron_variant	Intron 5 of 10	1		ENSP00000293826.4

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64422 AN: 151792 Hom.: 15299 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.432

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.424 AC: 64443 AN: 151912 Hom.: 15302 Cov.: 31 AF XY: 0.416 AC XY: 30894 AN XY: 74230

African (AFR) AF: 0.223 AC: 9253 AN: 41470

American (AMR) AF: 0.407 AC: 6205 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1608 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1969 AN: 5120

South Asian (SAS) AF: 0.331 AC: 1594 AN: 4818

European-Finnish (FIN) AF: 0.456 AC: 4813 AN: 10560

Middle Eastern (MID) AF: 0.340 AC: 98 AN: 288

European-Non Finnish (NFE) AF: 0.552 AC: 37460 AN: 67922

Other (OTH) AF: 0.431 AC: 907 AN: 2106

Alfa AF: 0.479 Hom.: 2294

Bravo AF: 0.416

Asia WGS AF: 0.348 AC: 1211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.21
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs12937543; hg19: chr17-7458582;