1-1211863-A-C

Variant names:

• chr1-1211863-A-C
• rs2298211
• NM_003327.4:c.635-31T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003327.4(TNFRSF4):​c.635-31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,519,710 control chromosomes in the GnomAD database, including 6,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (605 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6073 hom.)
• Consequence: TNFRSF4 NM_003327.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.141
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-1211863-A-C is Benign according to our data. Variant chr1-1211863-A-C is described in ClinVar as Benign. ClinVar VariationId is 1243792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF4	NM_003327.4	c.635-31T>G		intron_variant	Intron 5 of 6	ENST00000379236.4	NP_003318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF4	ENST00000379236.4	c.635-31T>G		intron_variant	Intron 5 of 6	1	NM_003327.4	ENSP00000368538.3

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12613 AN: 152030 Hom.: 605 Cov.: 33

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0833

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.0751

GnomAD2 exomes AF: 0.0808 AC: 9948 AN: 123148 AF XY: 0.0816

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.0959

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0915 AC: 125095 AN: 1367562 Hom.: 6073 Cov.: 31 AF XY: 0.0911 AC XY: 61358 AN XY: 673550

African (AFR) AF: 0.0678 AC: 2099 AN: 30962

American (AMR) AF: 0.0462 AC: 1468 AN: 31760

Ashkenazi Jewish (ASJ) AF: 0.0696 AC: 1620 AN: 23266

East Asian (EAS) AF: 0.145 AC: 5219 AN: 35992

South Asian (SAS) AF: 0.0813 AC: 6201 AN: 76254

European-Finnish (FIN) AF: 0.0951 AC: 3598 AN: 37838

Middle Eastern (MID) AF: 0.0785 AC: 399 AN: 5084

European-Non Finnish (NFE) AF: 0.0928 AC: 99262 AN: 1069704

Other (OTH) AF: 0.0922 AC: 5229 AN: 56702

GnomAD4 genome AF: 0.0829 AC: 12611 AN: 152148 Hom.: 605 Cov.: 33 AF XY: 0.0840 AC XY: 6250 AN XY: 74384

African (AFR) AF: 0.0682 AC: 2830 AN: 41524

American (AMR) AF: 0.0546 AC: 835 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3470

East Asian (EAS) AF: 0.148 AC: 763 AN: 5150

South Asian (SAS) AF: 0.0823 AC: 397 AN: 4824

European-Finnish (FIN) AF: 0.0923 AC: 980 AN: 10620

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6289 AN: 67946

Other (OTH) AF: 0.0739 AC: 156 AN: 2112

Alfa AF: 0.0896 Hom.: 125

Bravo AF: 0.0809

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs2298211; hg19: chr1-1147243; COSMIC: COSV64879334; COSMIC: COSV64879334;