rs2738787

Positions:

• chr20-63697022-A-G
• chr20-63697022-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003823.4(TNFRSF6B):​c.255A>G​(p.Leu85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 1,608,204 control chromosomes in the GnomAD database, including 693,083 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68093 hom., cov: 33)
  • Exomes 𝑓: 0.93 (624990 hom.)
• Consequence: TNFRSF6B NM_003823.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.41

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 20-63697022-A-G is Benign according to our data. Variant chr20-63697022-A-G is described in ClinVar as [Benign]. Clinvar id is 403404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF6B	NM_003823.4	c.255A>G	p.Leu85=	synonymous_variant	1/3	ENST00000369996.3	NP_003814.1
RTEL1-TNFRSF6B	NR_037882.1	n.4989A>G		non_coding_transcript_exon_variant	36/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF6B	ENST00000369996.3	c.255A>G	p.Leu85=	synonymous_variant	1/3	1	NM_003823.4	ENSP00000359013	P1
RTEL1-TNFRSF6B	ENST00000697815.1	n.2909A>G		non_coding_transcript_exon_variant	13/15

Frequencies

GnomAD3 genomes AF: 0.945 AC: 143781 AN: 152104 Hom.: 68027 Cov.: 33

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.956

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.948

GnomAD3 exomes AF: 0.939 AC: 222157 AN: 236582 Hom.: 104387 AF XY: 0.939 AC XY: 121765 AN XY: 129742

Gnomad AFR exome AF: 0.987

Gnomad AMR exome AF: 0.936

Gnomad ASJ exome AF: 0.958

Gnomad EAS exome AF: 0.995

Gnomad SAS exome AF: 0.948

Gnomad FIN exome AF: 0.939

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.935

GnomAD4 exome AF: 0.926 AC: 1348675 AN: 1455982 Hom.: 624990 Cov.: 110 AF XY: 0.927 AC XY: 671434 AN XY: 724560

Gnomad4 AFR exome AF: 0.987

Gnomad4 AMR exome AF: 0.940

Gnomad4 ASJ exome AF: 0.956

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.949

Gnomad4 FIN exome AF: 0.938

Gnomad4 NFE exome AF: 0.918

Gnomad4 OTH exome AF: 0.937

GnomAD4 genome AF: 0.945 AC: 143906 AN: 152222 Hom.: 68093 Cov.: 33 AF XY: 0.945 AC XY: 70352 AN XY: 74418

Gnomad4 AFR AF: 0.985

Gnomad4 AMR AF: 0.940

Gnomad4 ASJ AF: 0.956

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.918

Gnomad4 OTH AF: 0.948

Alfa AF: 0.926 Hom.: 27199

Bravo AF: 0.948

Asia WGS AF: 0.965 AC: 3356 AN: 3478

EpiCase AF: 0.918

EpiControl AF: 0.923

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Dyskeratosis congenita, autosomal recessive 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2738787; hg19: chr20-62328375; COSMIC: COSV53926796; COSMIC: COSV53926796;