1-7920925-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_001561.6(TNFRSF9):c.680-3_680-2insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,499,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: TNFRSF9 NM_001561.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.222

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-7920925-T-TA is Benign according to our data. Variant chr1-7920925-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 1165231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00235 (3172/1349392) while in subpopulation NFE AF= 0.00256 (2651/1034194). AF 95% confidence interval is 0.00248. There are 0 homozygotes in gnomad4_exome. There are 1532 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF9	NM_001561.6	c.680-3_680-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377507.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF9	ENST00000377507.8	c.680-3_680-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001561.6	P1

Frequencies

GnomAD3 genomes AF: 0.000266 AC: 40 AN: 150276 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000459

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00235 AC: 3172 AN: 1349392 Hom.: 0 Cov.: 28 AF XY: 0.00228 AC XY: 1532 AN XY: 670612

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.00170

Gnomad4 EAS exome AF: 0.00112

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.000266 AC: 40 AN: 150392 Hom.: 0 Cov.: 31 AF XY: 0.000273 AC XY: 20 AN XY: 73350

Gnomad4 AFR AF: 0.0000975

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000295

Gnomad4 NFE AF: 0.000459

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TNFRSF9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs767796238; hg19: chr1-7980985;