8-23224767-C-G

Variant names:

• chr8-23224767-C-G
• rs765900944
• NM_003844.4:c.295G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003844.4(TNFRSF10A):​c.295G>C​(p.Val99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12771302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	NM_003844.4	MANE Select	c.295G>C	p.Val99Leu	missense	Exon 1 of 10	NP_003835.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.295G>C	p.Val99Leu	missense	Exon 1 of 10	ENSP00000221132.3	O00220
	TNFRSF10A	ENST00000613472.1	TSL:1	c.31+264G>C		intron	N/A	ENSP00000480778.1	F8U8C0
	TNFRSF10A	ENST00000901503.1		c.295G>C	p.Val99Leu	missense	Exon 1 of 9	ENSP00000571562.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414728 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699180

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.00 AC: 0 AN: 36972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 37714

South Asian (SAS) AF: 0.00 AC: 0 AN: 80504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088028

Other (OTH) AF: 0.00 AC: 0 AN: 58586

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.8
DANN	Benign	0.90
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.11
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.24
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.019	D
Polyphen		0.76	P
Vest4		0.17
MutPred		0.45		Loss of sheet (P = 0.0084)
MVP		0.44
MPC		0.064
ClinPred		0.15	T
GERP RS		0.30
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.056
gMVP		0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs765900944; hg19: chr8-23082280;