1-1211644-G-A

Variant names:

• chr1-1211644-G-A
• rs34945898
• NM_003327.4:c.764-19C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001410709.1(TNFRSF4):​c.823C>T​(p.Leu275Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,563,318 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (48 hom.)
• Consequence: TNFRSF4 NM_001410709.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.251
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-1211644-G-A is Benign according to our data. Variant chr1-1211644-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1168816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410709.1. 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.764-19C>T		intron	N/A	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.823C>T	p.Leu275Phe	missense	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.764-19C>T		intron	N/A	ENSP00000368538.3	P43489
	TNFRSF4	ENST00000699974.1		c.823C>T	p.Leu275Phe	missense	Exon 6 of 6	ENSP00000514730.1	A0A8V8TQH5
	TNFRSF4	ENST00000699971.1		c.873-19C>T		intron	N/A	ENSP00000514728.1	A0A8V8TP52

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 844 AN: 152134 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00802

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00488 AC: 998 AN: 204708 AF XY: 0.00496

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00447

Gnomad ASJ exome AF: 0.00158

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00738

Gnomad OTH exome AF: 0.00665

GnomAD4 exome AF: 0.00737 AC: 10395 AN: 1411066 Hom.: 48 Cov.: 30 AF XY: 0.00721 AC XY: 5037 AN XY: 698526

African (AFR) AF: 0.00127 AC: 39 AN: 30798

American (AMR) AF: 0.00417 AC: 148 AN: 35514

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 40 AN: 23406

East Asian (EAS) AF: 0.00 AC: 0 AN: 37644

South Asian (SAS) AF: 0.00266 AC: 214 AN: 80454

European-Finnish (FIN) AF: 0.00302 AC: 155 AN: 51386

Middle Eastern (MID) AF: 0.00431 AC: 24 AN: 5564

European-Non Finnish (NFE) AF: 0.00865 AC: 9410 AN: 1088404

Other (OTH) AF: 0.00630 AC: 365 AN: 57896

GnomAD4 genome AF: 0.00554 AC: 844 AN: 152252 Hom.: 7 Cov.: 33 AF XY: 0.00525 AC XY: 391 AN XY: 74442

African (AFR) AF: 0.00205 AC: 85 AN: 41556

American (AMR) AF: 0.00751 AC: 115 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00802 AC: 545 AN: 67978

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00596

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Combined immunodeficiency due to OX40 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.25
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: rs34945898; hg19: chr1-1147024;