1-1203940-C-A

Variant names:

• chr1-1203940-C-A
• rs200096730
• ENST00000328596.10:c.419G>T

Variant summary

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

The NM_148901.2(TNFRSF18):​c.419G>T​(p.Arg140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. R140H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFRSF18 NM_148901.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 0 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=0.078680485).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148901.2. 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.630G>T	p.Pro210Pro	synonymous	Exon 5 of 5	NP_004186.1	Q9Y5U5-1
	TNFRSF18	NM_148901.2		c.419G>T	p.Arg140Leu	missense	Exon 4 of 4	NP_683699.1	Q9Y5U5-2
	TNFRSF18	NM_148902.2		c.609G>T	p.Pro203Pro	synonymous	Exon 5 of 5	NP_683700.1	Q9Y5U5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF18	ENST00000328596.10	TSL:1	c.419G>T	p.Arg140Leu	missense	Exon 4 of 4	ENSP00000328207.6	Q9Y5U5-2
	TNFRSF18	ENST00000379268.7	TSL:1 MANE Select	c.630G>T	p.Pro210Pro	synonymous	Exon 5 of 5	ENSP00000368570.2	Q9Y5U5-1
	TNFRSF18	ENST00000379265.5	TSL:1	c.609G>T	p.Pro203Pro	synonymous	Exon 5 of 5	ENSP00000368567.5	Q9Y5U5-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454898 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110966

Other (OTH) AF: 0.00 AC: 0 AN: 60228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.41
DANN	Benign	0.72
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.36	T
Polyphen		0.33	B
Vest4		0.21
MutPred		0.28		Gain of sheet (P = 0.0043)
MVP		0.081
MPC		0.028
ClinPred		0.59	D
GERP RS		-4.3
gMVP		0.53
Mutation Taster		=100/0	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: rs200096730; hg19: chr1-1139320;