rs114577645

Variant names:

• chr17-7550934-A-G
• rs114577645
• NM_003809.3:c.338-9A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003809.3(TNFSF12):​c.338-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,076 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (57 hom.)
• Consequence: TNFSF12 NM_003809.3 intron
• Scores: Splicing: ADA: 0.00006401
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0220
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-7550934-A-G is Benign according to our data. Variant chr17-7550934-A-G is described in ClinVar as Benign. ClinVar VariationId is 455755.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

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.338-9A>G		intron	N/A	NP_003800.1
	TNFSF12-TNFSF13	NM_172089.4		c.338-9A>G		intron	N/A	NP_742086.1
	TNFSF12	NR_037146.2		n.434-9A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF12	ENST00000293825.11	TSL:1 MANE Select	c.338-9A>G		intron	N/A	ENSP00000293825.6
	TNFSF12-TNFSF13	ENST00000293826.4	TSL:1	c.338-9A>G		intron	N/A	ENSP00000293826.4
	TNFSF12	ENST00000322272.11	TSL:1	n.338-9A>G		intron	N/A	ENSP00000314636.7

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2346 AN: 152092 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00424 AC: 1054 AN: 248854 AF XY: 0.00307

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00172 AC: 2517 AN: 1461866 Hom.: 57 Cov.: 32 AF XY: 0.00149 AC XY: 1080 AN XY: 727242

African (AFR) AF: 0.0589 AC: 1973 AN: 33478

American (AMR) AF: 0.00342 AC: 153 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1112002

Other (OTH) AF: 0.00334 AC: 202 AN: 60394

GnomAD4 genome AF: 0.0154 AC: 2348 AN: 152210 Hom.: 49 Cov.: 32 AF XY: 0.0152 AC XY: 1130 AN XY: 74424

African (AFR) AF: 0.0529 AC: 2194 AN: 41512

American (AMR) AF: 0.00772 AC: 118 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68018

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00831 Hom.: 7

Bravo AF: 0.0181

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Common variable immunodeficiency (1)
-	-	1	TNFSF12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.7
DANN	Benign	0.67
PhyloP100		0.022
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs114577645; hg19: chr17-7454251;