Genetic Variant TNFRSF9:c.*557T>C (chr1-7920278-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001561.6(TNFRSF9):c.*557T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 149,436 control chromosomes in the GnomAD database, including 7,038 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 0.20 ( 7038 hom., cov: 31)

Exomes 𝑓: 0.011 ( 0 hom. )

Consequence

TNFRSF9
NM_001561.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.70

Publications

13 publications found

Variant links:

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: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

TNFRSF9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001561.6. 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
	TNFRSF9	NM_001561.6	MANE Select	c.*557T>C		3_prime_UTR	Exon 8 of 8	NP_001552.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF9	ENST00000377507.8	TSL:1 MANE Select	c.*557T>C		3_prime_UTR	Exon 8 of 8	ENSP00000366729.3	Q07011
	TNFRSF9	ENST00000875592.1		c.*557T>C		downstream_gene	N/A	ENSP00000545651.1

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

30376

AN:

149160

Hom.:

7013

Cov.:

show subpopulations

Gnomad AFR

AF:

0.528

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.514

Gnomad SAS

AF:

0.0610

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.0710

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.171

GnomAD4 exome

AF:

0.0105

AC:

AN:

190

Hom.:

Cov.:

AF XY:

0.00943

AC XY:

AN XY:

106

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00725

AC:

AN:

138

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.204

AC:

30461

AN:

149246

Hom.:

7038

Cov.:

AF XY:

0.205

AC XY:

14894

AN XY:

72750

show subpopulations

African (AFR)

AF:

0.529

AC:

21320

AN:

40334

American (AMR)

AF:

0.264

AC:

3960

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.0536

AC:

185

AN:

3450

East Asian (EAS)

AF:

0.514

AC:

2636

AN:

5126

South Asian (SAS)

AF:

0.0610

AC:

288

AN:

4724

European-Finnish (FIN)

AF:

0.0137

AC:

135

AN:

9848

Middle Eastern (MID)

AF:

0.0729

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0231

AC:

1559

AN:

67522

Other (OTH)

AF:

0.172

AC:

356

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

769

1538

2307

3076

3845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.103

Hom.:

6649

Bravo

AF:

0.245

Asia WGS

AF:

0.327

AC:

1137

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.12

(source)

DANN

Benign

0.50

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over