8-23027251-T-C

Variant names:

• chr8-23027251-T-C
• NM_003842.5:c.818A>G

Variant summary

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

The NM_003842.5(TNFRSF10B):​c.818A>G​(p.Asn273Ser) 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 1,461,884 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: 6.8e-7 (0 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

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=0.14920458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF10B	NM_003842.5	c.818A>G	p.Asn273Ser	missense_variant	Exon 7 of 9	ENST00000276431.9	NP_003833.4
TNFRSF10B	NM_147187.3	c.731A>G	p.Asn244Ser	missense_variant	Exon 8 of 10		NP_671716.2
TNFRSF10B	NR_027140.2	n.762A>G		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.818A>G	p.Asn273Ser	missense_variant	Exon 7 of 9	1	NM_003842.5	ENSP00000276431.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

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

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.731A>G (p.N244S) alteration is located in exon 8 (coding exon 8) of the TNFRSF10B gene. This alteration results from a A to G substitution at nucleotide position 731, causing the asparagine (N) at amino acid position 244 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.77
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.092
Sift	Benign	0.064	T;T
Sift4G	Uncertain	0.030	D;D
Polyphen		0.13	B;P
Vest4		0.26
MutPred		0.21		Gain of phosphorylation at N273 (P = 0.0658);.;
MVP		0.94
MPC		0.056
ClinPred		0.18	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.089

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-22884764;