8-23027221-T-C

Variant names:

• chr8-23027221-T-C
• rs767495528
• NM_003842.5:c.848A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003842.5(TNFRSF10B):​c.848A>G​(p.Gln283Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000068 (1 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610
• Publications: 0 publications found

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]

TNFRSF10B Gene-Disease associations (from GenCC):

• head and neck squamous cell carcinoma

  Inheritance: Unknown, AD, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10462859).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003842.5. 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
	TNFRSF10B	NM_003842.5	MANE Select	c.848A>G	p.Gln283Arg	missense	Exon 7 of 9	NP_003833.4
	TNFRSF10B	NM_147187.3		c.761A>G	p.Gln254Arg	missense	Exon 8 of 10	NP_671716.2	O14763-2
	TNFRSF10B	NR_027140.2		n.792A>G		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10B	ENST00000276431.9	TSL:1 MANE Select	c.848A>G	p.Gln283Arg	missense	Exon 7 of 9	ENSP00000276431.4	O14763-1
	TNFRSF10B	ENST00000347739.3	TSL:1	c.761A>G	p.Gln254Arg	missense	Exon 8 of 10	ENSP00000317859.3	O14763-2
	TNFRSF10B	ENST00000523752.5	TSL:1	n.315A>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251276 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.7
DANN	Benign	0.50
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.061
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Benign	0.86	T
Sift4G	Benign	0.40	T
Polyphen		0.97	D
Vest4		0.083
MutPred		0.18		Gain of loop (P = 0.1069)
MVP		0.73
MPC		0.30
ClinPred		0.99	D
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs767495528; hg19: chr8-22884734;