Genetic Variant ENST00000328596.10:c.658C>T (chr1-1203701-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000328596.10(TNFRSF18):c.658C>T(p.Arg220Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,138 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

TNFRSF18
ENST00000328596.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Publications

0 publications found

Variant links:

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]

TNFRSF18 links:

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ACMG classification

Classification was made for transcript

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=0.03449732).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000328596.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF18	NM_004195.3	MANE Select	c.*143C>T		3_prime_UTR	Exon 5 of 5	NP_004186.1	Q9Y5U5-1
TNFRSF18	NM_148901.2		c.658C>T	p.Arg220Cys	missense	Exon 4 of 4	NP_683699.1	Q9Y5U5-2
TNFRSF18	NM_148902.2		c.*143C>T		3_prime_UTR	Exon 5 of 5	NP_683700.1	Q9Y5U5-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF18	ENST00000328596.10	TSL:1	c.658C>T	p.Arg220Cys	missense	Exon 4 of 4	ENSP00000328207.6	Q9Y5U5-2
TNFRSF18	ENST00000379268.7	TSL:1 MANE Select	c.*143C>T		3_prime_UTR	Exon 5 of 5	ENSP00000368570.2	Q9Y5U5-1
TNFRSF18	ENST00000379265.5	TSL:1	c.*143C>T		downstream_gene	N/A	ENSP00000368567.5	Q9Y5U5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000550

AC:

AN:

181884

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000425

AC:

AN:

1410138

Hom.:

Cov.:

AF XY:

0.00000573

AC XY:

AN XY:

697964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32646

American (AMR)

AF:

0.00

AC:

AN:

40624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24540

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38286

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5434

European-Non Finnish (NFE)

AF:

0.00000366

AC:

AN:

1091878

Other (OTH)

AF:

0.00

AC:

AN:

58524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000836

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.1

(source)

DANN

Benign

0.96

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.47

M_CAP

Benign

0.0056

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.99

PhyloP100

-1.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.050

Polyphen

0.0010

Vest4

0.13

MutPred

0.19

Loss of MoRF binding (P = 0.0495)

MVP

0.040

MPC

0.058

ClinPred

0.071

GERP RS

-3.3

gMVP

0.097

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over