1-7938903-T-A

Variant names:

• chr1-7938903-T-A
• rs226476
• NM_001561.6:c.101-75A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001561.6(TNFRSF9):​c.101-75A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 861,164 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: TNFRSF9 NM_001561.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 0 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: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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.101-75A>T		intron	N/A	NP_001552.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF9	ENST00000377507.8	TSL:1 MANE Select	c.101-75A>T		intron	N/A	ENSP00000366729.3	Q07011
	TNFRSF9	ENST00000875592.1		c.101-75A>T		intron	N/A	ENSP00000545651.1
	TNFRSF9	ENST00000674210.1		c.101-75A>T		intron	N/A	ENSP00000501326.1	A0A6I8PRR4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000116 AC: 1 AN: 861164 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 440520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20992

American (AMR) AF: 0.00 AC: 0 AN: 31770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19050

East Asian (EAS) AF: 0.00 AC: 0 AN: 35240

South Asian (SAS) AF: 0.00 AC: 0 AN: 58184

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 605270

Other (OTH) AF: 0.00 AC: 0 AN: 39036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.15
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs226476; hg19: chr1-7998963;