rs226478

Variant names:

• chr1-7936574-A-G
• rs226478
• NM_001561.6:c.413+1116T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF9	NM_001561.6	MANE Select	c.413+1116T>C		intron	N/A	NP_001552.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF9	ENST00000377507.8	TSL:1 MANE Select	c.413+1116T>C		intron	N/A	ENSP00000366729.3
	TNFRSF9	ENST00000492571.1	TSL:3	n.180-11T>C		intron	N/A	ENSP00000464978.1

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

GnomAD2 exomes AF: 1.00 AC: 8 AN: 8 AF XY: 1.00

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 12 AN: 12

South Asian (SAS) AF: 0.625 AC: 5 AN: 8

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.773 AC: 17 AN: 22

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.924 AC: 38410 AN: 41550

American (AMR) AF: 0.791 AC: 12097 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2077 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5184 AN: 5196

South Asian (SAS) AF: 0.783 AC: 3779 AN: 4828

European-Finnish (FIN) AF: 0.714 AC: 7560 AN: 10584

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45200 AN: 68002

Other (OTH) AF: 0.753 AC: 1592 AN: 2114

Alfa AF: 0.736 Hom.: 12286

Bravo AF: 0.781

Asia WGS AF: 0.900 AC: 3132 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.8
DANN	Benign	0.52
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs226478; hg19: chr1-7996634;