rs35160621

Variant names:

• chr1-1211585-G-A
• rs35160621
• NM_003327.4:c.804C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003327.4(TNFRSF4):​c.804C>T​(p.Ala268Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,519,314 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: TNFRSF4 NM_003327.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -11.3
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 1-1211585-G-A is Benign according to our data. Variant chr1-1211585-G-A is described in ClinVar as Benign. ClinVar VariationId is 474798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-11.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00524 (797/152180) while in subpopulation AFR AF = 0.0183 (761/41536). AF 95% confidence interval is 0.0172. There are 6 homozygotes in GnomAd4. There are 376 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.804C>T	p.Ala268Ala	synonymous	Exon 7 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.882C>T	p.Ala294Ala	synonymous	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.804C>T	p.Ala268Ala	synonymous	Exon 7 of 7	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699971.1		c.913C>T	p.Arg305*	stop_gained	Exon 6 of 6	ENSP00000514728.1	A0A8V8TP52
	TNFRSF4	ENST00000699976.1		c.607C>T	p.Arg203*	stop_gained	Exon 6 of 6	ENSP00000514732.1	A0A8V8TQV7

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 798 AN: 152062 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00158 AC: 274 AN: 173932 AF XY: 0.00105

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000706

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000762

GnomAD4 exome AF: 0.000489 AC: 668 AN: 1367134 Hom.: 6 Cov.: 30 AF XY: 0.000401 AC XY: 269 AN XY: 671524

African (AFR) AF: 0.0172 AC: 503 AN: 29298

American (AMR) AF: 0.000879 AC: 26 AN: 29566

Ashkenazi Jewish (ASJ) AF: 0.0000490 AC: 1 AN: 20424

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36832

South Asian (SAS) AF: 0.000138 AC: 10 AN: 72610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50060

Middle Eastern (MID) AF: 0.000375 AC: 2 AN: 5340

European-Non Finnish (NFE) AF: 0.0000637 AC: 68 AN: 1066920

Other (OTH) AF: 0.00102 AC: 57 AN: 56084

GnomAD4 genome AF: 0.00524 AC: 797 AN: 152180 Hom.: 6 Cov.: 33 AF XY: 0.00505 AC XY: 376 AN XY: 74418

African (AFR) AF: 0.0183 AC: 761 AN: 41536

American (AMR) AF: 0.00124 AC: 19 AN: 15290

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67970

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00403 Hom.: 0

Bravo AF: 0.00598

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	-1.0
CADD	Benign	0.049
DANN	Benign	0.59
PhyloP100		-11
Mutation Taster		=100/0	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: rs35160621; hg19: chr1-1146965; COSMIC: COSV64878794; COSMIC: COSV64878794;