1-1203598-C-G

Variant names:

• chr1-1203598-C-G
• rs1321296237
• ENST00000328596.10:c.761G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_148901.2(TNFRSF18):​c.761G>C​(p.Gly254Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,365,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TNFRSF18 NM_148901.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0110

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06645292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*246G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.761G>C	p.Gly254Ala	missense_variant	Exon 4 of 4		NP_683699.1
TNFRSF18	XM_017002722.3	c.1037G>C	p.Gly346Ala	missense_variant	Exon 4 of 4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*246G>C		3_prime_UTR_variant	Exon 5 of 5		NP_683700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000328596.10	c.761G>C	p.Gly254Ala	missense_variant	Exon 4 of 4	1		ENSP00000328207.6
TNFRSF18	ENST00000379268	c.*246G>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_004195.3	ENSP00000368570.2
TNFRSF18	ENST00000379265.5	c.*246G>C		downstream_gene_variant		1		ENSP00000368567.5
TNFRSF18	ENST00000486728.5	c.*246G>C		downstream_gene_variant		1		ENSP00000462735.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000592 AC: 1 AN: 168918 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 91450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000640

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1365090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 670856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761G>C (p.G254A) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a G to C substitution at nucleotide position 761, causing the glycine (G) at amino acid position 254 to be replaced by an alanine (A). 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
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Uncertain	0.98
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.064
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.46	P
Vest4		0.27
MutPred		0.093		Gain of stability (P = 0.0159);
MVP		0.092
MPC		0.16
ClinPred		0.79	D
GERP RS		-2.9
gMVP		0.074

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: rs1321296237; hg19: chr1-1138978;