rs114577645

Positions:

• chr17-7550934-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003809.3(TNFSF12):​c.338-9A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006401
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0220

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF12	NM_003809.3	c.338-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000293825.11
TNFSF12-TNFSF13	NM_172089.4	c.338-9A>G		splice_polypyrimidine_tract_variant, intron_variant
TNFSF12	NR_037146.2	n.434-9A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF12	ENST00000293825.11	c.338-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003809.3	P4

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

GnomAD3 exomes AF: 0.00424 AC: 1054 AN: 248854 Hom.: 17 AF XY: 0.00307 AC XY: 413 AN XY: 134712

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.00334

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

Gnomad4 AFR AF: 0.0529

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00780 Hom.: 5

Bravo AF: 0.0181

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

TNFSF12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Common variable immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.7
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs114577645; hg19: chr17-7454251;