NM_004195.3:c.679G>C

Variant names:

• chr1-1203891-C-G
• rs764023260
• NM_004195.3:c.679G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004195.3(TNFRSF18):​c.679G>C​(p.Glu227Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E227K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF18 NM_004195.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• Publications: 1 publications found

Genes affected

TNFRSF18 (HGNC:11914): (TNF receptor superfamily member 18) This gene encodes a member of the TNF-receptor superfamily. The encoded receptor has been shown to have increased expression upon T-cell activation, and it is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. Knockout studies in mice also suggest the role of this receptor is in the regulation of CD3-driven T-cell activation and programmed cell death. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Feb 2011]

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=0.19702545).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004195.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF18	NM_004195.3	MANE Select	c.679G>C	p.Glu227Gln	missense	Exon 5 of 5	NP_004186.1	Q9Y5U5-1
	TNFRSF18	NM_148902.2		c.658G>C	p.Glu220Gln	missense	Exon 5 of 5	NP_683700.1	Q9Y5U5-3
	TNFRSF18	NM_148901.2		c.468G>C	p.Ala156Ala	synonymous	Exon 4 of 4	NP_683699.1	Q9Y5U5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF18	ENST00000379268.7	TSL:1 MANE Select	c.679G>C	p.Glu227Gln	missense	Exon 5 of 5	ENSP00000368570.2	Q9Y5U5-1
	TNFRSF18	ENST00000379265.5	TSL:1	c.658G>C	p.Glu220Gln	missense	Exon 5 of 5	ENSP00000368567.5	Q9Y5U5-3
	TNFRSF18	ENST00000486728.5	TSL:1	c.463G>C	p.Glu155Gln	missense	Exon 4 of 4	ENSP00000462735.1	J3KT02

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.66	T
PhyloP100		4.1
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Benign	0.034	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.13		Gain of MoRF binding (P = 0.0561)
MVP		0.75
ClinPred		0.27	T
GERP RS		2.4
Varity_R		0.097
Mutation Taster		=94/6	polymorphism

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: rs764023260; hg19: chr1-1139271;