20-63696792-C-G

Variant names:

• chr20-63696792-C-G
• rs990360819
• NM_003823.4:c.25C>G

Variant summary

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

The NM_003823.4(TNFRSF6B):​c.25C>G​(p.Leu9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFRSF6B NM_003823.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691
• Publications: 0 publications found

Genes affected

TNFRSF6B (HGNC:11921): (TNF receptor superfamily member 6b) This gene belongs to the tumor necrosis factor receptor superfamily. The encoded protein is postulated to play a regulatory role in suppressing FasL- and LIGHT-mediated cell death. It acts as a decoy receptor that competes with death receptors for ligand binding. Over-expression of this gene has been noted in gastrointestinal tract tumors. Read-through transcription into this gene from the neighboring upstream gene, which encodes regulator of telomere elongation helicase 1 (RTEL1), generates a non-coding transcript. [provided by RefSeq, Feb 2011]

RTEL1-TNFRSF6B (HGNC:44095): (RTEL1-TNFRSF6B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RTEL1 (regulator of telomere elongation helicase 1) and TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

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=0.07459238).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003823.4. 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
	TNFRSF6B	NM_003823.4	MANE Select	c.25C>G	p.Leu9Val	missense	Exon 1 of 3	NP_003814.1	O95407
	RTEL1-TNFRSF6B	NR_037882.1		n.4759C>G		non_coding_transcript_exon	Exon 36 of 38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF6B	ENST00000369996.3	TSL:1 MANE Select	c.25C>G	p.Leu9Val	missense	Exon 1 of 3	ENSP00000359013.1	O95407
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1364C>G		non_coding_transcript_exon	Exon 33 of 35	ENSP00000457428.1	D6RA96
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1364C>G		3_prime_UTR	Exon 33 of 35	ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450980 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 720932

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25506

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 84706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107244

Other (OTH) AF: 0.00 AC: 0 AN: 59818

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.89
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.69
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.033
Sift	Benign	0.30	T
Sift4G	Benign	0.40	T
Polyphen		0.084	B
Vest4		0.11
MutPred		0.41		Loss of loop (P = 0.0804)
MVP		0.26
MPC		0.014
ClinPred		0.096	T
GERP RS		0.57
PromoterAI		-0.10	Neutral
Varity_R		0.069
gMVP		0.41
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs990360819; hg19: chr20-62328145;