Genetic Variant TNFRSF10B:p.Ala67Gly (chr8-23043188-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003842.5(TNFRSF10B):c.200C>G(p.Ala67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNFRSF10B
NM_003842.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.151

Publications

40 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28438458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF10B	NM_003842.5 link	c.200C>G	p.Ala67Gly	missense_variant	Exon 2 of 9	ENST00000276431.9	NP_003833.4	O14763-1Q7Z2I8
TNFRSF10B	NM_147187.3 link	c.200C>G	p.Ala67Gly	missense_variant	Exon 2 of 10		NP_671716.2	O14763-2
TNFRSF10B	NR_027140.2 link	n.282-12316C>G		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF10B	ENST00000276431.9 link	c.200C>G	p.Ala67Gly	missense_variant	Exon 2 of 9	1	NM_003842.5	ENSP00000276431.4		O14763-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

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:

33480

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.5

L;L

PhyloP100

-0.15

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;D

Vest4

0.11

MutPred

0.31

Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);

MVP

0.94

MPC

0.071

ClinPred

0.53

GERP RS

2.6

Varity_R

0.26

gMVP

0.37

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over