chr1-1213065-G-A

Variant names:

• chr1-1213065-G-A
• rs34160451
• NM_003327.4:c.297C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003327.4(TNFRSF4):​c.297C>T​(p.Cys99Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,610,736 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (31 hom., cov: 33)
  • Exomes 𝑓: 0.022 (414 hom.)
• Consequence: TNFRSF4 NM_003327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.174
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP6: Variant 1-1213065-G-A is Benign according to our data. Variant chr1-1213065-G-A is described in ClinVar as Benign. ClinVar VariationId is 474796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.174 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0157 (2394/152320) while in subpopulation NFE AF = 0.023 (1562/68000). AF 95% confidence interval is 0.022. There are 31 homozygotes in GnomAd4. There are 1197 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 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.297C>T	p.Cys99Cys	synonymous	Exon 3 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.297C>T	p.Cys99Cys	synonymous	Exon 3 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.297C>T	p.Cys99Cys	synonymous	Exon 3 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699971.1		c.297C>T	p.Cys99Cys	synonymous	Exon 3 of 6	ENSP00000514728.1	A0A8V8TP52
	TNFRSF4	ENST00000699974.1		c.297C>T	p.Cys99Cys	synonymous	Exon 3 of 6	ENSP00000514730.1	A0A8V8TQH5

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2394 AN: 152202 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0169 AC: 4031 AN: 238318 AF XY: 0.0171

Gnomad AFR exome AF: 0.00352

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0223 AC: 32553 AN: 1458416 Hom.: 414 Cov.: 32 AF XY: 0.0218 AC XY: 15792 AN XY: 725508

African (AFR) AF: 0.00293 AC: 98 AN: 33464

American (AMR) AF: 0.00514 AC: 229 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 412 AN: 26016

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00727 AC: 625 AN: 86022

European-Finnish (FIN) AF: 0.0398 AC: 2047 AN: 51480

Middle Eastern (MID) AF: 0.00591 AC: 34 AN: 5752

European-Non Finnish (NFE) AF: 0.0250 AC: 27815 AN: 1111240

Other (OTH) AF: 0.0215 AC: 1292 AN: 60232

GnomAD4 genome AF: 0.0157 AC: 2394 AN: 152320 Hom.: 31 Cov.: 33 AF XY: 0.0161 AC XY: 1197 AN XY: 74486

African (AFR) AF: 0.00399 AC: 166 AN: 41588

American (AMR) AF: 0.00705 AC: 108 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0411 AC: 437 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0230 AC: 1562 AN: 68000

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0195 Hom.: 26

Bravo AF: 0.0131

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0221

EpiControl AF: 0.0195

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.0
DANN	Benign	0.71
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34160451; hg19: chr1-1148445;