NM_003327.4:c.767G>C

Variant names:

• chr1-1211622-C-G
• rs1649106016
• NM_003327.4:c.767G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003327.4(TNFRSF4):​c.767G>C​(p.Gly256Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 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)
• Consequence: TNFRSF4 NM_003327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.359
• Publications: 0 publications found

Genes affected

TNFRSF4 (HGNC:11918): (TNF receptor superfamily member 4) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

TNFRSF4 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to OX40 deficiency

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003327.4. 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
	TNFRSF4	NM_003327.4	MANE Select	c.767G>C	p.Gly256Ala	missense	Exon 7 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.845G>C	p.Gly282Ala	missense	Exon 6 of 6	NP_001397638.1	A0A8V8TQH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF4	ENST00000379236.4	TSL:1 MANE Select	c.767G>C	p.Gly256Ala	missense	Exon 7 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699974.1		c.845G>C	p.Gly282Ala	missense	Exon 6 of 6	ENSP00000514730.1	A0A8V8TQH5
	TNFRSF4	ENST00000699969.1		c.830G>C	p.Gly277Ala	missense	Exon 6 of 6	ENSP00000514726.1	A0A8V8TPN6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to OX40 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.36
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.035	D
Sift4G	Uncertain	0.055	T
Polyphen		0.96	P
Vest4		0.095
MutPred		0.46		Loss of catalytic residue at S258 (P = 0.1187)
MVP		0.69
MPC		0.22
ClinPred		0.40	T
GERP RS		3.3
Varity_R		0.17
gMVP		0.36
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1649106016; hg19: chr1-1147002;