rs17568

Variant names:

• chr1-1212042-C-T
• rs17568
• NM_003327.4:c.534G>A
• TNFRSF4 p.Glu178Glu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003327.4(TNFRSF4):​c.534G>A​(p.Glu178Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,611,028 control chromosomes in the GnomAD database, including 76,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9219 hom., cov: 34)
  • Exomes 𝑓: 0.27 (67127 hom.)
• Consequence: TNFRSF4 NM_003327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00300
• Publications: 27 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: ClinGen, Orphanet, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP6: Variant 1-1212042-C-T is Benign according to our data. Variant chr1-1212042-C-T is described in ClinVar as Benign. ClinVar VariationId is 403556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

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.534G>A	p.Glu178Glu	synonymous	Exon 5 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.534G>A	p.Glu178Glu	synonymous	Exon 5 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.534G>A	p.Glu178Glu	synonymous	Exon 5 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699971.1		c.534G>A	p.Glu178Glu	synonymous	Exon 5 of 6	ENSP00000514728.1	A0A8V8TP52
	TNFRSF4	ENST00000699974.1		c.534G>A	p.Glu178Glu	synonymous	Exon 5 of 6	ENSP00000514730.1	A0A8V8TQH5

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48124 AN: 151944 Hom.: 9189 Cov.: 34

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.367 AC: 89404 AN: 243526 AF XY: 0.360

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.742

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.268 AC: 391246 AN: 1458966 Hom.: 67127 Cov.: 37 AF XY: 0.275 AC XY: 199321 AN XY: 725776

African (AFR) AF: 0.403 AC: 13464 AN: 33440

American (AMR) AF: 0.602 AC: 26779 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4822 AN: 25958

East Asian (EAS) AF: 0.768 AC: 30450 AN: 39668

South Asian (SAS) AF: 0.556 AC: 47889 AN: 86058

European-Finnish (FIN) AF: 0.232 AC: 12117 AN: 52140

Middle Eastern (MID) AF: 0.280 AC: 1611 AN: 5746

European-Non Finnish (NFE) AF: 0.212 AC: 236136 AN: 1111228

Other (OTH) AF: 0.298 AC: 17978 AN: 60280

GnomAD4 genome AF: 0.317 AC: 48202 AN: 152062 Hom.: 9219 Cov.: 34 AF XY: 0.326 AC XY: 24241 AN XY: 74328

African (AFR) AF: 0.394 AC: 16352 AN: 41464

American (AMR) AF: 0.460 AC: 7036 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 658 AN: 3470

East Asian (EAS) AF: 0.751 AC: 3860 AN: 5142

South Asian (SAS) AF: 0.580 AC: 2802 AN: 4832

European-Finnish (FIN) AF: 0.224 AC: 2379 AN: 10606

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14262 AN: 67942

Other (OTH) AF: 0.310 AC: 655 AN: 2116

Alfa AF: 0.241 Hom.: 2251

Bravo AF: 0.332

Asia WGS AF: 0.682 AC: 2366 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Combined immunodeficiency due to OX40 deficiency (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.6
DANN	Benign	0.68
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17568;

hg19: chr1-1147422;

COSMIC: COSV55420568;

COSMIC: COSV55420568;