17-7549491-G-C

Variant names:

• chr17-7549491-G-C
• rs868687352
• NM_003809.3:c.177G>C

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.177G>C​(p.Glu59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E59K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFSF12 NM_003809.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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=0.08561143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF12	NM_003809.3	c.177G>C	p.Glu59Asp	missense_variant	Exon 2 of 7	ENST00000293825.11	NP_003800.1
TNFSF12-TNFSF13	NM_172089.4	c.177G>C	p.Glu59Asp	missense_variant	Exon 2 of 11		NP_742086.1
TNFSF12	NR_037146.2	n.273G>C		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF12	ENST00000293825.11	c.177G>C	p.Glu59Asp	missense_variant	Exon 2 of 7	1	NM_003809.3	ENSP00000293825.6
TNFSF12-TNFSF13	ENST00000293826.4	c.177G>C	p.Glu59Asp	missense_variant	Exon 2 of 11	1		ENSP00000293826.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395820 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688286

African (AFR) AF: 0.0000621 AC: 2 AN: 32226

American (AMR) AF: 0.00 AC: 0 AN: 36216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24622

East Asian (EAS) AF: 0.00 AC: 0 AN: 36710

South Asian (SAS) AF: 0.00 AC: 0 AN: 78822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074688

Other (OTH) AF: 0.00 AC: 0 AN: 57604

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Common variable immunodeficiency Uncertain:1

Feb 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with TNFSF12-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 59 of the TNFSF12 protein (p.Glu59Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.1	L;.
PhyloP100		2.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0020	B;.
Vest4		0.12
MutPred		0.11		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.17
MPC		0.41
ClinPred		0.13	T
GERP RS		3.3
PromoterAI		-0.049	Neutral
Varity_R		0.073
gMVP		0.16
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs868687352; hg19: chr17-7452808;