6-31575828-G-T

Variant names:

• chr6-31575828-G-T
• rs2228088
• NM_000594.4:c.87G>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000594.4(TNF):​c.87G>T​(p.Arg29Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,612,698 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (54 hom.)
• Consequence: TNF NM_000594.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.641
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-31575828-G-T is Benign according to our data. Variant chr6-31575828-G-T is described in ClinVar as Benign. ClinVar VariationId is 784495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.641 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000594.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	NM_000594.4	MANE Select	c.87G>T	p.Arg29Arg	synonymous	Exon 1 of 4	NP_000585.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	ENST00000449264.3	TSL:1 MANE Select	c.87G>T	p.Arg29Arg	synonymous	Exon 1 of 4	ENSP00000398698.2
	TNF	ENST00000699334.1		c.87G>T	p.Arg29Arg	synonymous	Exon 1 of 3	ENSP00000514308.1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2299 AN: 152162 Hom.: 52 Cov.: 31

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00401 AC: 1001 AN: 249700 AF XY: 0.00325

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00160 AC: 2333 AN: 1460418 Hom.: 54 Cov.: 30 AF XY: 0.00138 AC XY: 1000 AN XY: 726580

African (AFR) AF: 0.0539 AC: 1798 AN: 33362

American (AMR) AF: 0.00341 AC: 152 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000604 AC: 52 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00504 AC: 29 AN: 5758

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111378

Other (OTH) AF: 0.00413 AC: 249 AN: 60316

GnomAD4 genome AF: 0.0151 AC: 2298 AN: 152280 Hom.: 51 Cov.: 31 AF XY: 0.0150 AC XY: 1116 AN XY: 74462

African (AFR) AF: 0.0520 AC: 2161 AN: 41546

American (AMR) AF: 0.00588 AC: 90 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00611 Hom.: 50

Bravo AF: 0.0173

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000596

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.81
PhyloP100		-0.64
PromoterAI		0.0014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228088; hg19: chr6-31543605;