rs35304565

Variant names:

• chr1-1214100-G-A
• rs35304565
• NM_003327.4:c.28C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1214100-G-A
• chr1-1214100-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003327.4(TNFRSF4):​c.28C>T​(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,585,918 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (95 hom.)
• Consequence: TNFRSF4 NM_003327.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.340
• Publications: 10 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: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057964325).
• BP6: Variant 1-1214100-G-A is Benign according to our data. Variant chr1-1214100-G-A is described in ClinVar as Benign. ClinVar VariationId is 474794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00527 (803/152330) while in subpopulation SAS AF = 0.0193 (93/4822). AF 95% confidence interval is 0.0161. There are 5 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown gene

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.28C>T	p.Arg10Cys	missense	Exon 1 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.28C>T	p.Arg10Cys	missense	Exon 1 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.28C>T	p.Arg10Cys	missense	Exon 1 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699971.1		c.28C>T	p.Arg10Cys	missense	Exon 1 of 6	ENSP00000514728.1	A0A8V8TP52
	TNFRSF4	ENST00000699974.1		c.28C>T	p.Arg10Cys	missense	Exon 1 of 6	ENSP00000514730.1	A0A8V8TQH5

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152212 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00679

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00854 AC: 1757 AN: 205672 AF XY: 0.00985

Gnomad AFR exome AF: 0.00206

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00848

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00796

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.00799 AC: 11452 AN: 1433588 Hom.: 95 Cov.: 34 AF XY: 0.00846 AC XY: 6023 AN XY: 711812

African (AFR) AF: 0.00154 AC: 51 AN: 33038

American (AMR) AF: 0.00335 AC: 141 AN: 42130

Ashkenazi Jewish (ASJ) AF: 0.00929 AC: 239 AN: 25720

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38874

South Asian (SAS) AF: 0.0244 AC: 2035 AN: 83548

European-Finnish (FIN) AF: 0.00580 AC: 251 AN: 43312

Middle Eastern (MID) AF: 0.0213 AC: 90 AN: 4234

European-Non Finnish (NFE) AF: 0.00736 AC: 8120 AN: 1103394

Other (OTH) AF: 0.00881 AC: 523 AN: 59338

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152330 Hom.: 5 Cov.: 33 AF XY: 0.00521 AC XY: 388 AN XY: 74486

African (AFR) AF: 0.00180 AC: 75 AN: 41582

American (AMR) AF: 0.00562 AC: 86 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4822

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00678 AC: 461 AN: 68018

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00712 Hom.: 4

Bravo AF: 0.00500

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00116 AC: 5

ESP6500EA AF: 0.00736 AC: 62

ExAC AF: 0.00785 AC: 932

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to OX40 deficiency (1)
-	-	1	not provided (1)
-	-	1	TNFRSF4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.34
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.16
MVP		0.62
MPC		0.20
ClinPred		0.016	T
GERP RS		2.2
PromoterAI		-0.058	Neutral
Varity_R		0.17
gMVP		0.84
Mutation Taster		=99/1	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: rs35304565; hg19: chr1-1149480; COSMIC: COSV55420573; COSMIC: COSV55420573;