1-7929506-C-T

Variant names:

• chr1-7929506-C-T
• rs2453021
• NM_001561.6:c.679+3656G>A

Variant summary

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

The NM_001561.6(TNFRSF9):​c.679+3656G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 151,864 control chromosomes in the GnomAD database, including 7,033 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 0.28 (7033 hom., cov: 30)
• Consequence: TNFRSF9 NM_001561.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.193
• Publications: 18 publications found

Genes affected

TNFRSF9 (HGNC:11924): (TNF receptor superfamily member 9) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

TNFRSF9 Gene-Disease associations (from GenCC):

• immunodeficiency 109 with lymphoproliferation

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF9	NM_001561.6	c.679+3656G>A		intron_variant	Intron 7 of 7	ENST00000377507.8	NP_001552.2
TNFRSF9	XM_006710618.4	c.679+3656G>A		intron_variant	Intron 7 of 7		XP_006710681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.679+3656G>A		intron_variant	Intron 7 of 7	1	NM_001561.6	ENSP00000366729.3
TNFRSF9	ENST00000474475.1	c.223+3656G>A		intron_variant	Intron 2 of 2	3		ENSP00000465272.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42778 AN: 151744 Hom.: 7035 Cov.: 30

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.323

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.282 AC: 42765 AN: 151864 Hom.: 7033 Cov.: 30 AF XY: 0.285 AC XY: 21138 AN XY: 74190

African (AFR) AF: 0.107 AC: 4416 AN: 41444

American (AMR) AF: 0.337 AC: 5128 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1280 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1655 AN: 5168

South Asian (SAS) AF: 0.416 AC: 2003 AN: 4818

European-Finnish (FIN) AF: 0.308 AC: 3240 AN: 10526

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23786 AN: 67908

Other (OTH) AF: 0.324 AC: 682 AN: 2104

Alfa AF: 0.329 Hom.: 12624

Bravo AF: 0.273

Asia WGS AF: 0.341 AC: 1186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.1
DANN	Benign	0.55
PhyloP100		0.19
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: rs2453021; hg19: chr1-7989566; COSMIC: COSV66348927; COSMIC: COSV66348927;