1-12104334-G-C

Variant names:

• chr1-12104334-G-C
• rs11569850
• NM_001243.5:c.269-45G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243.5(TNFRSF8):​c.269-45G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,610,680 control chromosomes in the GnomAD database, including 5,224 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.058 (344 hom., cov: 32)
  • Exomes 𝑓: 0.080 (4880 hom.)
• Consequence: TNFRSF8 NM_001243.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.635
• Publications: 4 publications found

Genes affected

TNFRSF8 (HGNC:11923): (TNF receptor superfamily member 8) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. This receptor is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF8	NM_001243.5	MANE Select	c.269-45G>C		intron	N/A	NP_001234.3
	TNFRSF8	NM_001281430.3		c.-65-45G>C		intron	N/A	NP_001268359.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF8	ENST00000263932.7	TSL:1 MANE Select	c.269-45G>C		intron	N/A	ENSP00000263932.2
	TNFRSF8	ENST00000417814.3	TSL:1	c.-65-45G>C		intron	N/A	ENSP00000390650.2
	TNFRSF8	ENST00000514649.5	TSL:1	n.*13-45G>C		intron	N/A	ENSP00000421938.1

Frequencies

GnomAD3 genomes AF: 0.0579 AC: 8806 AN: 152016 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.0373

Gnomad EAS AF: 0.0666

Gnomad SAS AF: 0.0782

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0556

GnomAD2 exomes AF: 0.0685 AC: 17174 AN: 250806 AF XY: 0.0693

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0829

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.0561

Gnomad FIN exome AF: 0.0671

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.0704

GnomAD4 exome AF: 0.0798 AC: 116346 AN: 1458544 Hom.: 4880 Cov.: 30 AF XY: 0.0795 AC XY: 57727 AN XY: 725776

African (AFR) AF: 0.0112 AC: 375 AN: 33400

American (AMR) AF: 0.0815 AC: 3644 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 956 AN: 26116

East Asian (EAS) AF: 0.0870 AC: 3450 AN: 39672

South Asian (SAS) AF: 0.0736 AC: 6339 AN: 86134

European-Finnish (FIN) AF: 0.0672 AC: 3588 AN: 53394

Middle Eastern (MID) AF: 0.0289 AC: 156 AN: 5404

European-Non Finnish (NFE) AF: 0.0844 AC: 93688 AN: 1109472

Other (OTH) AF: 0.0689 AC: 4150 AN: 60252

GnomAD4 genome AF: 0.0578 AC: 8801 AN: 152136 Hom.: 344 Cov.: 32 AF XY: 0.0573 AC XY: 4262 AN XY: 74384

African (AFR) AF: 0.0145 AC: 601 AN: 41506

American (AMR) AF: 0.0656 AC: 1003 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0373 AC: 129 AN: 3462

East Asian (EAS) AF: 0.0664 AC: 344 AN: 5184

South Asian (SAS) AF: 0.0773 AC: 372 AN: 4814

European-Finnish (FIN) AF: 0.0657 AC: 695 AN: 10584

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0807 AC: 5485 AN: 67988

Other (OTH) AF: 0.0550 AC: 116 AN: 2108

Alfa AF: 0.0315 Hom.: 30

Bravo AF: 0.0555

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.067
DANN	Benign	0.65
PhyloP100		-0.64
Mutation Taster		=98/1	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: rs11569850; hg19: chr1-12164391; COSMIC: COSV55801164;