20-63697022-A-T

Variant names:

• chr20-63697022-A-T
• rs2738787
• NM_003823.4:c.255A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM2 PP3_Moderate BP6_Moderate BP7

The NM_003823.4(TNFRSF6B):​c.255A>T​(p.Leu85Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L85L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFRSF6B NM_003823.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.41
• Publications: 25 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_noAF computational evidence supports a deleterious effect, 0.37
• BP6: Variant 20-63697022-A-T is Benign according to our data. Variant chr20-63697022-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1994954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.

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.255A>T	p.Leu85Leu	synonymous	Exon 1 of 3	NP_003814.1	O95407
	RTEL1-TNFRSF6B	NR_037882.1		n.4989A>T		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.255A>T	p.Leu85Leu	synonymous	Exon 1 of 3	ENSP00000359013.1	O95407
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1594A>T		non_coding_transcript_exon	Exon 33 of 35	ENSP00000457428.1	D6RA96
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1594A>T		3_prime_UTR	Exon 33 of 35	ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456014 Hom.: 0 Cov.: 110 AF XY: 0.00 AC XY: 0 AN XY: 724576

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111582

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 40260

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	17
DANN	Uncertain	1.0
PhyloP100		2.4
PromoterAI		-0.0029	Neutral

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: rs2738787; hg19: chr20-62328375;