rs2257440

Variant names:

• chr20-63696914-C-T
• rs2257440
• NM_003823.4:c.147C>T
• TNFRSF6B p.Cys49Cys

Your query was ambiguous. Multiple possible variants found:

• chr20-63696914-C-T
• chr20-63696914-C-A
• chr20-63696914-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_003823.4(TNFRSF6B):​c.147C>T​(p.Cys49Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,608,974 control chromosomes in the GnomAD database, including 52,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3883 hom., cov: 34)
  • Exomes 𝑓: 0.25 (49069 hom.)
• Consequence: TNFRSF6B NM_003823.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.886
• Publications: 35 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.272).
• BP6: Variant 20-63696914-C-T is Benign according to our data. Variant chr20-63696914-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.886 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

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.147C>T	p.Cys49Cys	synonymous	Exon 1 of 3	NP_003814.1	O95407
	RTEL1-TNFRSF6B	NR_037882.1		n.4881C>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.147C>T	p.Cys49Cys	synonymous	Exon 1 of 3	ENSP00000359013.1	O95407
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1486C>T		non_coding_transcript_exon	Exon 33 of 35	ENSP00000457428.1	D6RA96
	RTEL1-TNFRSF6B	ENST00000492259.6	TSL:5	n.*1486C>T		3_prime_UTR	Exon 33 of 35	ENSP00000457428.1	D6RA96

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29483 AN: 152104 Hom.: 3886 Cov.: 34

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.253 AC: 58764 AN: 232054 AF XY: 0.252

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.247 AC: 360526 AN: 1456752 Hom.: 49069 Cov.: 33 AF XY: 0.248 AC XY: 179419 AN XY: 724452

African (AFR) AF: 0.0506 AC: 1691 AN: 33426

American (AMR) AF: 0.248 AC: 11006 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6206 AN: 26056

East Asian (EAS) AF: 0.623 AC: 24643 AN: 39544

South Asian (SAS) AF: 0.255 AC: 21950 AN: 85986

European-Finnish (FIN) AF: 0.201 AC: 10256 AN: 51150

Middle Eastern (MID) AF: 0.201 AC: 1152 AN: 5744

European-Non Finnish (NFE) AF: 0.242 AC: 268588 AN: 1110422

Other (OTH) AF: 0.250 AC: 15034 AN: 60076

GnomAD4 genome AF: 0.194 AC: 29482 AN: 152222 Hom.: 3883 Cov.: 34 AF XY: 0.196 AC XY: 14607 AN XY: 74404

African (AFR) AF: 0.0621 AC: 2580 AN: 41568

American (AMR) AF: 0.210 AC: 3220 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 835 AN: 3472

East Asian (EAS) AF: 0.625 AC: 3216 AN: 5142

South Asian (SAS) AF: 0.263 AC: 1270 AN: 4826

European-Finnish (FIN) AF: 0.202 AC: 2141 AN: 10610

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15542 AN: 67976

Other (OTH) AF: 0.197 AC: 416 AN: 2114

Alfa AF: 0.216 Hom.: 1278

Bravo AF: 0.192

Asia WGS AF: 0.402 AC: 1395 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.75
DANN	Benign	0.93
PhyloP100		-0.89
PromoterAI		0.013	Neutral
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2257440;

hg19: chr20-62328267;

COSMIC: COSV53926555;

COSMIC: COSV53926555;