17-7556854-C-T

Variant names:

• chr17-7556854-C-T
• rs147597489
• NM_003809.3:c.450C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_003809.3(TNFSF12):​c.450C>T​(p.Ile150Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000931 in 1,556,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: TNFSF12 NM_003809.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.15
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-7556854-C-T is Benign according to our data. Variant chr17-7556854-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 526012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF12	NM_003809.3	c.450C>T	p.Ile150Ile	synonymous_variant	Exon 6 of 7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4	c.450C>T	p.Ile150Ile	synonymous_variant	Exon 6 of 11		NP_742086.1
TNFSF12	NR_037146.2	n.785C>T		non_coding_transcript_exon_variant	Exon 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11	c.450C>T	p.Ile150Ile	synonymous_variant	Exon 6 of 7	1	NM_003809.3	ENSP00000293825.6
TNFSF12-TNFSF13	ENST00000293826.4	c.450C>T	p.Ile150Ile	synonymous_variant	Exon 6 of 11	1		ENSP00000293826.4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000823 AC: 17 AN: 206592 AF XY: 0.0000902

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000740

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.0000933 AC: 131 AN: 1404742 Hom.: 1 Cov.: 31 AF XY: 0.000108 AC XY: 75 AN XY: 692394

African (AFR) AF: 0.0000316 AC: 1 AN: 31626

American (AMR) AF: 0.000110 AC: 4 AN: 36422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22798

East Asian (EAS) AF: 0.00 AC: 0 AN: 38896

South Asian (SAS) AF: 0.000331 AC: 26 AN: 78538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.0000888 AC: 96 AN: 1081164

Other (OTH) AF: 0.0000692 AC: 4 AN: 57790

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74310

African (AFR) AF: 0.0000967 AC: 4 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Common variable immunodeficiency Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.6
DANN	Benign	0.84
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147597489; hg19: chr17-7460171;