8-23191958-G-T

Position:

• chr8-23191958-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003844.4(TNFRSF10A):​c.1143C>A​(p.Asp381Glu) 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: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051475674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4	c.1143C>A	p.Asp381Glu	missense_variant	10/10	ENST00000221132.8	NP_003835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.1143C>A	p.Asp381Glu	missense_variant	10/10	1	NM_003844.4	ENSP00000221132.3
TNFRSF10A	ENST00000613472.1	c.669C>A	p.Asp223Glu	missense_variant	9/9	1		ENSP00000480778.1
TNFRSF10A	ENST00000519862.1	n.198C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Aug 09, 2021

The c.1143C>A (p.D381E) alteration is located in exon 10 (coding exon 10) of the TNFRSF10A gene. This alteration results from a C to A substitution at nucleotide position 1143, causing the aspartic acid (D) at amino acid position 381 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.023
DANN	Benign	0.57
DEOGEN2	Benign	0.066	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.32	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.17
Sift	Benign	0.72	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.14	B;.
Vest4		0.030
MutPred		0.65		Loss of loop (P = 0.0128);.;
MVP		0.21
MPC		0.12
ClinPred		0.053	T
GERP RS		-4.2
Varity_R		0.044
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1297649662; hg19: chr8-23049471;