Genetic Variant TNFRSF10B:c.780+126T>A (chr8-23027596-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003842.5(TNFRSF10B):c.780+126T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,197,032 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: 31)

Exomes 𝑓: 8.4e-7 ( 0 hom. )

Consequence

TNFRSF10B
NM_003842.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.326

Publications

2 publications found

Variant links:

Genes affected

TNFRSF10B (HGNC:11905): (TNF receptor superfamily member 10b) The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene. [provided by RefSeq, Mar 2009]

TNFRSF10B Gene-Disease associations (from GenCC):

head and neck squamous cell carcinoma
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TNFRSF10B links:

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ACMG classification

Classification was made for transcript

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=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003842.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TNFRSF10B	NM_003842.5	MANE Select	c.780+126T>A	intron	N/A	NP_003833.4
TNFRSF10B	NM_147187.3		c.693+126T>A	intron	N/A	NP_671716.2
TNFRSF10B	NR_027140.2		n.724+126T>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TNFRSF10B	ENST00000276431.9	TSL:1 MANE Select	c.780+126T>A	intron	N/A	ENSP00000276431.4
TNFRSF10B	ENST00000347739.3	TSL:1	c.693+126T>A	intron	N/A	ENSP00000317859.3
TNFRSF10B	ENST00000523752.5	TSL:1	n.247+126T>A	intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.35e-7

AC:

AN:

1197032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

604364

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27876

American (AMR)

AF:

0.00

AC:

AN:

39154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22938

East Asian (EAS)

AF:

0.00

AC:

AN:

37398

South Asian (SAS)

AF:

0.00

AC:

AN:

77522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00000112

AC:

AN:

890832

Other (OTH)

AF:

0.00

AC:

AN:

51732

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.4

(source)

DANN

Benign

0.82

PhyloP100

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over