chr8-23028334-A-T

Position:

• chr8-23028334-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003842.5(TNFRSF10B):​c.745T>A​(p.Ser249Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.711

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14729509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10B	NM_003842.5	c.745T>A	p.Ser249Thr	missense_variant	5/9	ENST00000276431.9
TNFRSF10B	NM_147187.3	c.658T>A	p.Ser220Thr	missense_variant	6/10
TNFRSF10B	NR_027140.2	n.689T>A		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.745T>A	p.Ser249Thr	missense_variant	5/9	1	NM_003842.5	P2
TNFRSF10B	ENST00000347739.3	c.658T>A	p.Ser220Thr	missense_variant	6/10	1		A2
TNFRSF10B	ENST00000518531.5	n.495T>A		non_coding_transcript_exon_variant	3/3	3
TNFRSF10B	ENST00000523504.5	c.*279T>A		3_prime_UTR_variant, NMD_transcript_variant	5/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 29, 2023

The c.658T>A (p.S220T) alteration is located in exon 6 (coding exon 6) of the TNFRSF10B gene. This alteration results from a T to A substitution at nucleotide position 658, causing the serine (S) at amino acid position 220 to be replaced by a threonine (T). 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	0.094
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.6
DANN	Benign	0.91
DEOGEN2	Benign	0.085	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.20
Sift	Benign	0.076	T;T
Sift4G	Uncertain	0.024	D;D
Polyphen		0.90	P;D
Vest4		0.075
MutPred		0.36		Loss of disorder (P = 0.0727);.;
MVP		0.87
MPC		0.34
ClinPred		0.53	D
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.089
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-22885847;