Genetic Variant NM_000594.4:c.121G>T (chr6-31575862-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000594.4(TNF):c.121G>T(p.Val41Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TNF
NM_000594.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

Variant links:

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]

TNF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.070076406).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNF	NM_000594.4 link	c.121G>T	p.Val41Leu	missense_variant	Exon 1 of 4	ENST00000449264.3	NP_000585.2	P01375Q5STB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3 link	c.121G>T	p.Val41Leu	missense_variant	Exon 1 of 4	1	NM_000594.4	ENSP00000398698.2		P01375
TNF	ENST00000699334.1 link	c.121G>T	p.Val41Leu	missense_variant	Exon 1 of 3			ENSP00000514308.1		A0A8V8TNL2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000324

AC:

AN:

246804

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000628

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458600

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121G>T (p.V41L) alteration is located in exon 1 (coding exon 1) of the TNF gene. This alteration results from a G to T substitution at nucleotide position 121, causing the valine (V) at amino acid position 41 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.065

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.056

M_CAP

Benign

0.010

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.040

REVEL

Benign

0.12

Sift

Benign

0.62

Sift4G

Benign

0.22

Polyphen

0.0040

Vest4

0.064

MutPred

0.37

Loss of catalytic residue at V41 (P = 0.0134);

MVP

0.87

MPC

0.55

ClinPred

0.070

GERP RS

3.9

Varity_R

0.078

gMVP

0.40

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over