1-1203891-C-T

Variant names:

• chr1-1203891-C-T
• rs764023260
• NM_004195.3:c.679G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004195.3(TNFRSF18):​c.679G>A​(p.Glu227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,605,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0000062 (0 hom.)
• Consequence: TNFRSF18 NM_004195.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.08
• Publications: 1 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20804808).
• BP6: Variant 1-1203891-C-T is Benign according to our data. Variant chr1-1203891-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3180255.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.679G>A	p.Glu227Lys	missense	Exon 5 of 5	NP_004186.1	Q9Y5U5-1
	TNFRSF18	NM_148902.2		c.658G>A	p.Glu220Lys	missense	Exon 5 of 5	NP_683700.1	Q9Y5U5-3
	TNFRSF18	NM_148901.2		c.468G>A	p.Ala156Ala	synonymous	Exon 4 of 4	NP_683699.1	Q9Y5U5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF18	ENST00000379268.7	TSL:1 MANE Select	c.679G>A	p.Glu227Lys	missense	Exon 5 of 5	ENSP00000368570.2	Q9Y5U5-1
	TNFRSF18	ENST00000379265.5	TSL:1	c.658G>A	p.Glu220Lys	missense	Exon 5 of 5	ENSP00000368567.5	Q9Y5U5-3
	TNFRSF18	ENST00000486728.5	TSL:1	c.463G>A	p.Glu155Lys	missense	Exon 4 of 4	ENSP00000462735.1	J3KT02

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233344 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000619 AC: 9 AN: 1453472 Hom.: 0 Cov.: 33 AF XY: 0.00000691 AC XY: 5 AN XY: 723162

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.0000225 AC: 1 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47106

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111030

Other (OTH) AF: 0.0000166 AC: 1 AN: 60210

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

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

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000833 AC: 1

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	0.19
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.68	T
PhyloP100		4.1
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.20		Gain of ubiquitination at E227 (P = 0.0048)
MVP		0.71
ClinPred		0.28	T
GERP RS		2.4
Varity_R		0.13
Mutation Taster		=93/7	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: rs764023260; hg19: chr1-1139271;