rs9657980

Variant names:

• chr1-7934973-A-G
• rs9657980
• NM_001561.6:c.544+40T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001561.6(TNFRSF9):​c.544+40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,609,826 control chromosomes in the GnomAD database, including 466 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 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.022 (434 hom.)
• Consequence: TNFRSF9 NM_001561.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.523
• Publications: 1 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=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0151 (2295/152336) while in subpopulation NFE AF = 0.0262 (1782/68018). AF 95% confidence interval is 0.0252. There are 32 homozygotes in GnomAd4. There are 1039 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF9	NM_001561.6	c.544+40T>C		intron_variant	Intron 6 of 7	ENST00000377507.8	NP_001552.2
TNFRSF9	XM_006710618.4	c.544+40T>C		intron_variant	Intron 6 of 7		XP_006710681.1
TNFRSF9	XM_047419672.1	c.544+40T>C		intron_variant	Intron 6 of 7		XP_047275628.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.544+40T>C		intron_variant	Intron 6 of 7	1	NM_001561.6	ENSP00000366729.3
TNFRSF9	ENST00000474475.1	c.88+40T>C		intron_variant	Intron 1 of 2	3		ENSP00000465272.1
TNFRSF9	ENST00000492571.1	n.*186+40T>C		intron_variant	Intron 4 of 4	3		ENSP00000464978.1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2296 AN: 152218 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0163 AC: 4037 AN: 247322 AF XY: 0.0161

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00371

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0220 AC: 32112 AN: 1457490 Hom.: 434 Cov.: 30 AF XY: 0.0213 AC XY: 15426 AN XY: 724828

African (AFR) AF: 0.00327 AC: 109 AN: 33336

American (AMR) AF: 0.00431 AC: 189 AN: 43808

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 115 AN: 25826

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39628

South Asian (SAS) AF: 0.00978 AC: 838 AN: 85654

European-Finnish (FIN) AF: 0.0176 AC: 939 AN: 53326

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5746

European-Non Finnish (NFE) AF: 0.0260 AC: 28882 AN: 1109988

Other (OTH) AF: 0.0172 AC: 1035 AN: 60178

GnomAD4 genome AF: 0.0151 AC: 2295 AN: 152336 Hom.: 32 Cov.: 32 AF XY: 0.0139 AC XY: 1039 AN XY: 74502

African (AFR) AF: 0.00430 AC: 179 AN: 41584

American (AMR) AF: 0.00477 AC: 73 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0262 AC: 1782 AN: 68018

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0187 Hom.: 8

Bravo AF: 0.0137

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.072
DANN	Benign	0.34
PhyloP100		-0.52
PromoterAI		0.0076	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9657980; hg19: chr1-7995033;