6-31577385-G-C

Position:

• chr6-31577385-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000594.4(TNF):​c.550G>C​(p.Gly184Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNF NM_000594.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

TNF (HGNC:11892): (tumor necrosis factor) This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33317167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNF	NM_000594.4	c.550G>C	p.Gly184Arg	missense_variant	4/4	ENST00000449264.3	NP_000585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3	c.550G>C	p.Gly184Arg	missense_variant	4/4	1	NM_000594.4	ENSP00000398698.2
TNF	ENST00000699334.1	c.*282G>C		3_prime_UTR_variant	3/3			ENSP00000514308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.550G>C (p.G184R) alteration is located in exon 4 (coding exon 4) of the TNF gene. This alteration results from a G to C substitution at nucleotide position 550, causing the glycine (G) at amino acid position 184 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.33	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.038	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.011	D
Polyphen		0.49	P
Vest4		0.15
MutPred		0.41		Gain of solvent accessibility (P = 0.0037);
MVP		1.0
MPC		0.78
ClinPred		0.65	D
GERP RS		2.5
Varity_R		0.23
gMVP		0.76

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31545162;