rs226478

Positions:

• chr1-7936574-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001561.6(TNFRSF9):​c.413+1116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 152,288 control chromosomes in the GnomAD database, including 45,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.77 (45941 hom., cov: 33)
  • Exomes 𝑓: 0.80 (14 hom.)
• Consequence: TNFRSF9 NM_001561.6 intron
• Scores: Splicing: ADA: 0.00001597
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.00

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 1-7936574-A-G is Benign according to our data. Variant chr1-7936574-A-G is described in ClinVar as [Benign]. Clinvar id is 2688454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF9	NM_001561.6	c.413+1116T>C		intron_variant		ENST00000377507.8
TNFRSF9	XM_006710618.4	c.413+1116T>C		intron_variant
TNFRSF9	XM_047419672.1	c.413+1116T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.413+1116T>C		intron_variant		1	NM_001561.6	P1
TNFRSF9	ENST00000492571.1	c.180-11T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116630 AN: 152126 Hom.: 45875 Cov.: 33

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.748

GnomAD3 exomes AF: 1.00 AC: 8 AN: 8 Hom.: 4 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad NFE exome AF: 1.00

GnomAD4 exome AF: 0.795 AC: 35 AN: 44 Hom.: 14 Cov.: 0 AF XY: 0.813 AC XY: 26 AN XY: 32

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.625

Gnomad4 NFE exome AF: 0.773

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.767 AC: 116756 AN: 152244 Hom.: 45941 Cov.: 33 AF XY: 0.770 AC XY: 57339 AN XY: 74420

Gnomad4 AFR AF: 0.924

Gnomad4 AMR AF: 0.791

Gnomad4 ASJ AF: 0.598

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.753

Alfa AF: 0.723 Hom.: 5170

Bravo AF: 0.781

Asia WGS AF: 0.900 AC: 3132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 94% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.8
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs226478; hg19: chr1-7996634;