6-31576785-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000594.4(TNF):c.251C>T(p.Pro84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,612,964 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (22 hom.)
• Consequence: TNF NM_000594.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.178

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046066046).
• BP6: Variant 6-31576785-C-T is Benign according to our data. Variant chr6-31576785-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 781865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00183 (2680/1460774) while in subpopulation MID AF= 0.0184 (106/5768). AF 95% confidence interval is 0.0155. There are 22 homozygotes in gnomad4_exome. There are 1446 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 249 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNF	NM_000594.4	c.251C>T	p.Pro84Leu	missense_variant	3/4	ENST00000449264.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNF	ENST00000449264.3	c.251C>T	p.Pro84Leu	missense_variant	3/4	1	NM_000594.4	P1
TNF	ENST00000699334.1	c.205C>T	p.Arg69Ter	stop_gained	2/3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152072 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00256 AC: 632 AN: 246682 Hom.: 7 AF XY: 0.00280 AC XY: 377 AN XY: 134420

Gnomad AFR exome AF: 0.000265

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00983

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00494

GnomAD4 exome AF: 0.00183 AC: 2680 AN: 1460774 Hom.: 22 Cov.: 32 AF XY: 0.00199 AC XY: 1446 AN XY: 726702

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00454

Gnomad4 FIN exome AF: 0.000172

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152190 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74394

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00235 Hom.: 4

Bravo AF: 0.00163

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00295 AC: 16

ExAC AF: 0.00235 AC: 280

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TNF: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.045	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.30	T
Polyphen		0.0070	B
Vest4		0.056
MVP		0.97
MPC		0.57
ClinPred		0.033	T
GERP RS		0.019
Varity_R		0.12
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs4645843; hg19: chr6-31544562; COSMIC: COSV69304800; COSMIC: COSV69304800;