1-6461487-C-G

Position:

• chr1-6461487-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003790.3(TNFRSF25):​c.1201G>C​(p.Gly401Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF25 NM_003790.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

Genes affected

TNFRSF25 (HGNC:11910): (TNF receptor superfamily member 25) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially in the tissues enriched in lymphocytes, and it may play a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Knockout studies in mice suggested the role of this gene in the removal of self-reactive T cells in the thymus. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF25	NM_003790.3	c.1201G>C	p.Gly401Arg	missense_variant	10/10	ENST00000356876.8	NP_003781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF25	ENST00000356876.8	c.1201G>C	p.Gly401Arg	missense_variant	10/10	1	NM_003790.3	ENSP00000349341	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Mar 30, 2024

The c.1228G>C (p.G410R) alteration is located in exon 10 (coding exon 10) of the TNFRSF25 gene. This alteration results from a G to C substitution at nucleotide position 1228, causing the glycine (G) at amino acid position 410 to be replaced by an arginine (R). 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
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;.;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.69	.;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	.;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	.;D;D;D;D;D
Sift4G	Uncertain	0.013	.;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;D
Vest4		0.43, 0.41, 0.43, 0.54, 0.53
MutPred		0.67		.;.;Gain of MoRF binding (P = 0.0218);.;.;.;
MVP		0.96
MPC		2.6
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6521547;