chr8-23028342-C-A

Position:

• chr8-23028342-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_003842.5(TNFRSF10B):​c.737G>T​(p.Gly246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.193

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1313588).
• BS2: High AC in GnomAdExome4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10B	NM_003842.5	c.737G>T	p.Gly246Val	missense_variant	5/9	ENST00000276431.9
TNFRSF10B	NM_147187.3	c.650G>T	p.Gly217Val	missense_variant	6/10
TNFRSF10B	NR_027140.2	n.681G>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.737G>T	p.Gly246Val	missense_variant	5/9	1	NM_003842.5	P2
TNFRSF10B	ENST00000347739.3	c.650G>T	p.Gly217Val	missense_variant	6/10	1		A2
TNFRSF10B	ENST00000518531.5	n.487G>T		non_coding_transcript_exon_variant	3/3	3
TNFRSF10B	ENST00000523504.5	c.*271G>T		3_prime_UTR_variant, NMD_transcript_variant	5/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.650G>T (p.G217V) alteration is located in exon 6 (coding exon 6) of the TNFRSF10B gene. This alteration results from a G to T substitution at nucleotide position 650, causing the glycine (G) at amino acid position 217 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.0
DANN	Benign	0.58
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.15
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;B
Vest4		0.15
MutPred		0.54		Gain of sheet (P = 0.0344);.;
MVP		0.90
MPC		0.078
ClinPred		0.060	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779594561; hg19: chr8-22885855;