1-1213724-C-T

Variant names:

• chr1-1213724-C-T
• rs555467061
• NM_003327.4:c.207G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_003327.4(TNFRSF4):​c.207G>A​(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,600,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: TNFRSF4 NM_003327.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.41
• 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-1213724-C-T is Benign according to our data. Variant chr1-1213724-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 541650.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.41 with no splicing effect.

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.207G>A	p.Pro69Pro	synonymous	Exon 2 of 7	NP_003318.1
	TNFRSF4	NM_001410709.1		c.207G>A	p.Pro69Pro	synonymous	Exon 2 of 6	NP_001397638.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF4	ENST00000379236.4	TSL:1 MANE Select	c.207G>A	p.Pro69Pro	synonymous	Exon 2 of 7	ENSP00000368538.3
	TNFRSF4	ENST00000699971.1		c.207G>A	p.Pro69Pro	synonymous	Exon 2 of 6	ENSP00000514728.1
	TNFRSF4	ENST00000699974.1		c.207G>A	p.Pro69Pro	synonymous	Exon 2 of 6	ENSP00000514730.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000583 AC: 13 AN: 222834 AF XY: 0.0000661

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000605

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000801 AC: 116 AN: 1448348 Hom.: 0 Cov.: 32 AF XY: 0.0000792 AC XY: 57 AN XY: 719298

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.0000233 AC: 1 AN: 42984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39004

South Asian (SAS) AF: 0.000191 AC: 16 AN: 83894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000840 AC: 93 AN: 1106854

Other (OTH) AF: 0.000100 AC: 6 AN: 59840

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to OX40 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.78
PhyloP100		-2.4
PromoterAI		0.044	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs555467061; hg19: chr1-1149104;