1-1203694-C-G

Position:

• chr1-1203694-C-G

Variant summary

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

The ENST00000328596.10(TNFRSF18):​c.665G>C​(p.Gly222Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TNFRSF18 ENST00000328596.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.58

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=0.0496715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*150G>C		3_prime_UTR_variant	5/5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.665G>C	p.Gly222Ala	missense_variant	4/4		NP_683699.1
TNFRSF18	XM_017002722.3	c.941G>C	p.Gly314Ala	missense_variant	4/4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*150G>C		3_prime_UTR_variant	5/5		NP_683700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF18	ENST00000328596.10	c.665G>C	p.Gly222Ala	missense_variant	4/4	1		ENSP00000328207
TNFRSF18	ENST00000379268.7	c.*150G>C		3_prime_UTR_variant	5/5	1	NM_004195.3	ENSP00000368570	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.665G>C (p.G222A) 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 665, causing the glycine (G) at amino acid position 222 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	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.6
DANN	Uncertain	0.98
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.33	B
Vest4		0.14
MutPred		0.12		Loss of catalytic residue at G222 (P = 0.0271);
MVP		0.099
MPC		0.18
ClinPred		0.35	T
GERP RS		-0.36
gMVP		0.054

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: rs1001151157; hg19: chr1-1139074;