1-1203820-G-A

Variant names:

• chr1-1203820-G-A
• rs371611084
• ENST00000328596.10:c.539C>T

Variant summary

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

The NM_148901.2(TNFRSF18):​c.539C>T​(p.Pro180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000461 in 1,582,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: TNFRSF18 NM_148901.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.743

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=0.026540726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF18	NM_004195.3	c.*24C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000379268.7	NP_004186.1
TNFRSF18	NM_148901.2	c.539C>T	p.Pro180Leu	missense_variant	Exon 4 of 4		NP_683699.1
TNFRSF18	XM_017002722.3	c.815C>T	p.Pro272Leu	missense_variant	Exon 4 of 4		XP_016858211.1
TNFRSF18	NM_148902.2	c.*24C>T		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.539C>T	p.Pro180Leu	missense_variant	Exon 4 of 4	1		ENSP00000328207.6
TNFRSF18	ENST00000379268	c.*24C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_004195.3	ENSP00000368570.2
TNFRSF18	ENST00000379265.5	c.*24C>T		downstream_gene_variant		1		ENSP00000368567.5
TNFRSF18	ENST00000486728.5	c.*24C>T		downstream_gene_variant		1		ENSP00000462735.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000608 AC: 12 AN: 197496 Hom.: 0 AF XY: 0.0000458 AC XY: 5 AN XY: 109136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000193

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000130

Gnomad SAS exome AF: 0.0000370

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000341

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000434 AC: 62 AN: 1429724 Hom.: 0 Cov.: 33 AF XY: 0.0000394 AC XY: 28 AN XY: 710084

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000156

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000236

Gnomad4 OTH exome AF: 0.000219

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74470

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000254 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539C>T (p.P180L) alteration is located in exon 4 (coding exon 4) of the TNFRSF18 gene. This alteration results from a C to T substitution at nucleotide position 539, causing the proline (P) at amino acid position 180 to be replaced by a leucine (L). 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	-0.55	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.87
DANN	Benign	0.54
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.055
MPC		0.022
ClinPred		0.017	T
GERP RS		-2.7
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371611084; hg19: chr1-1139200;