rs763921252

Variant names:

• chr1-1203884-G-A
• rs763921252
• NM_004195.3:c.686C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1203884-G-A
• chr1-1203884-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004195.3(TNFRSF18):​c.686C>T​(p.Ser229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,604,162 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TNFRSF18 NM_004195.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.491
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04188019).
• BP6: Variant 1-1203884-G-A is Benign according to our data. Variant chr1-1203884-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3971368.Status of the report is criteria_provided_single_submitter, 1 stars.

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.686C>T	p.Ser229Leu	missense	Exon 5 of 5	NP_004186.1	Q9Y5U5-1
	TNFRSF18	NM_148901.2		c.475C>T	p.Arg159Trp	missense	Exon 4 of 4	NP_683699.1	Q9Y5U5-2
	TNFRSF18	NM_148902.2		c.665C>T	p.Ser222Leu	missense	Exon 5 of 5	NP_683700.1	Q9Y5U5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF18	ENST00000379268.7	TSL:1 MANE Select	c.686C>T	p.Ser229Leu	missense	Exon 5 of 5	ENSP00000368570.2	Q9Y5U5-1
	TNFRSF18	ENST00000328596.10	TSL:1	c.475C>T	p.Arg159Trp	missense	Exon 4 of 4	ENSP00000328207.6	Q9Y5U5-2
	TNFRSF18	ENST00000379265.5	TSL:1	c.665C>T	p.Ser222Leu	missense	Exon 5 of 5	ENSP00000368567.5	Q9Y5U5-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000475 AC: 11 AN: 231356 AF XY: 0.0000394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0000597

Gnomad NFE exome AF: 0.0000770

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000269 AC: 39 AN: 1452002 Hom.: 0 Cov.: 33 AF XY: 0.0000318 AC XY: 23 AN XY: 722302

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39590

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85522

European-Finnish (FIN) AF: 0.0000644 AC: 3 AN: 46596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1110630

Other (OTH) AF: 0.0000499 AC: 3 AN: 60142

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74320

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

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000750 AC: 9

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.15
DANN	Benign	0.75
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.49
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.061
Sift	Benign	0.052	T
Sift4G	Benign	0.063	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.14		Loss of loop (P = 0.0153)
MVP		0.055
MPC		0.022
ClinPred		0.011	T
GERP RS		-1.3
Varity_R		0.026
gMVP		0.36
Mutation Taster		=98/2	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: rs763921252; hg19: chr1-1139264; COSMIC: COSV60775094;