rs226476

Positions:

• chr1-7938903-T-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.101-75A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,013,220 control chromosomes in the GnomAD database, including 472,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.97 (72084 hom., cov: 33)
  • Exomes 𝑓: 0.96 (400647 hom.)
• Consequence: TNFRSF9 NM_001561.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.290

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=-0.92).
• BP6: Variant 1-7938903-T-G is Benign according to our data. Variant chr1-7938903-T-G is described in ClinVar as [Benign]. Clinvar id is 2688134.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF9	NM_001561.6	c.101-75A>C		intron_variant		ENST00000377507.8
TNFRSF9	XM_006710618.4	c.101-75A>C		intron_variant
TNFRSF9	XM_047419672.1	c.101-75A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.101-75A>C		intron_variant		1	NM_001561.6	P1
TNFRSF9	ENST00000674210.1	c.101-75A>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.972 AC: 148033 AN: 152228 Hom.: 72024 Cov.: 33

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.958

Gnomad OTH AF: 0.977

GnomAD4 exome AF: 0.965 AC: 830397 AN: 860874 Hom.: 400647 AF XY: 0.965 AC XY: 425073 AN XY: 440396

Gnomad4 AFR exome AF: 0.994

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.972

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.940

Gnomad4 NFE exome AF: 0.959

Gnomad4 OTH exome AF: 0.967

GnomAD4 genome AF: 0.972 AC: 148152 AN: 152346 Hom.: 72084 Cov.: 33 AF XY: 0.973 AC XY: 72469 AN XY: 74496

Gnomad4 AFR AF: 0.994

Gnomad4 AMR AF: 0.985

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.991

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.958

Gnomad4 OTH AF: 0.977

Alfa AF: 0.963 Hom.: 36107

Bravo AF: 0.977

Asia WGS AF: 0.996 AC: 3464 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 47% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.5
DANN	Benign	0.22

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

LitVar

Other links and lift over

dbSNP: rs226476; hg19: chr1-7998963;