1-1211577-T-C

Variant names:

• chr1-1211577-T-C
• rs1336408361
• NM_003327.4:c.812A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003327.4(TNFRSF4):​c.812A>G​(p.His271Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000599 in 1,503,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: TNFRSF4 NM_003327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.393
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14087507).

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.812A>G	p.His271Arg	missense	Exon 7 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.890A>G	p.His297Arg	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.812A>G	p.His271Arg	missense	Exon 7 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699974.1		c.890A>G	p.His297Arg	missense	Exon 6 of 6	ENSP00000514730.1	A0A8V8TQH5
	TNFRSF4	ENST00000699969.1		c.875A>G	p.His292Arg	missense	Exon 6 of 6	ENSP00000514726.1	A0A8V8TPN6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151040 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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000518 AC: 7 AN: 1352074 Hom.: 0 Cov.: 30 AF XY: 0.00000302 AC XY: 2 AN XY: 662678

African (AFR) AF: 0.00 AC: 0 AN: 28674

American (AMR) AF: 0.00 AC: 0 AN: 27568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19848

East Asian (EAS) AF: 0.00 AC: 0 AN: 35928

South Asian (SAS) AF: 0.00 AC: 0 AN: 70236

European-Finnish (FIN) AF: 0.0000403 AC: 2 AN: 49608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5284

European-Non Finnish (NFE) AF: 0.00000472 AC: 5 AN: 1059492

Other (OTH) AF: 0.00 AC: 0 AN: 55436

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151040 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73734

African (AFR) AF: 0.00 AC: 0 AN: 40966

American (AMR) AF: 0.00 AC: 0 AN: 15222

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67728

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to OX40 deficiency (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.39
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.097
Sift	Benign	0.16	T
Sift4G	Uncertain	0.053	T
Polyphen		0.68	P
Vest4		0.11
MVP		0.61
MPC		0.46
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.099
gMVP		0.31
Mutation Taster		=95/5	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: rs1336408361; hg19: chr1-1146957;