chr20-63696799-T-G

Position:

• chr20-63696799-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003823.4(TNFRSF6B):​c.32T>G​(p.Leu11Arg) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L11L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TNFRSF6B NM_003823.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.466

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14172187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF6B	NM_003823.4	c.32T>G	p.Leu11Arg	missense_variant	1/3	ENST00000369996.3
RTEL1-TNFRSF6B	NR_037882.1	n.4766T>G		non_coding_transcript_exon_variant	36/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF6B	ENST00000369996.3	c.32T>G	p.Leu11Arg	missense_variant	1/3	1	NM_003823.4	P1
RTEL1-TNFRSF6B	ENST00000697815.1	n.2686T>G		non_coding_transcript_exon_variant	13/15

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

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

Apr 18, 2023

The c.32T>G (p.L11R) alteration is located in exon 1 (coding exon 1) of the TNFRSF6B gene. This alteration results from a T to G substitution at nucleotide position 32, causing the leucine (L) at amino acid position 11 to be replaced by an arginine (R). 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	0.093
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.2
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.092
Sift	Benign	0.043	D
Sift4G	Uncertain	0.025	D
Polyphen		0.0040	B
Vest4		0.22
MutPred		0.71		Loss of helix (P = 0.0033);
MVP		0.44
MPC		0.014
ClinPred		0.051	T
GERP RS		-1.3
Varity_R		0.11
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62328152;