8-23224874-C-T

Position:

• chr8-23224874-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_003844.4(TNFRSF10A):​c.188G>A​(p.Gly63Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,427,282 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: 30)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

Genes affected

TNFRSF10A (HGNC:11904): (TNF receptor superfamily member 10a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. [provided by RefSeq, Jul 2008]

TNFRSF10A-DT (HGNC:52647): (TNFRSF10A divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11185202).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4	c.188G>A	p.Gly63Glu	missense_variant	1/10	ENST00000221132.8	NP_003835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.188G>A	p.Gly63Glu	missense_variant	1/10	1	NM_003844.4	ENSP00000221132	P1
TNFRSF10A	ENST00000613472.1	c.31+157G>A		intron_variant		1		ENSP00000480778
TNFRSF10A-DT	ENST00000517774.1	n.404C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1427282 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706874

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: 0.00000365

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

Oct 02, 2023

The c.188G>A (p.G63E) alteration is located in exon 1 (coding exon 1) of the TNFRSF10A gene. This alteration results from a G to A substitution at nucleotide position 188, causing the glycine (G) at amino acid position 63 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.6
DANN	Benign	0.91
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Benign	0.44	T
Polyphen		0.90	P
Vest4		0.064
MutPred		0.26		Loss of MoRF binding (P = 0.0428);
MVP		0.52
MPC		0.12
ClinPred		0.45	T
GERP RS		0.49
Varity_R		0.11
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1801316873; hg19: chr8-23082387;