rs12480346

Variant names:

• chr20-63692927-C-T
• rs12480346
• NM_001283009.2:c.2775C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-63692927-C-T
• chr20-63692927-C-A
• chr20-63692927-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001283009.2(RTEL1):​c.2775C>T​(p.Ser925Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,612,652 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (90 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.53
• Publications: 3 publications found

Genes affected

RTEL1 (HGNC:15888): (regulator of telomere elongation helicase 1) This gene encodes a DNA helicase which functions in the stability, protection and elongation of telomeres and interacts with proteins in the shelterin complex known to protect telomeres during DNA replication. Mutations in this gene have been associated with dyskeratosis congenita and Hoyerall-Hreidarsson syndrome. Read-through transcription of this gene into the neighboring downstream gene, which encodes tumor necrosis factor receptor superfamily, member 6b, generates a non-coding transcript. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-63692927-C-T is Benign according to our data. Variant chr20-63692927-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00442 (673/152326) while in subpopulation AMR AF = 0.0341 (522/15296). AF 95% confidence interval is 0.0317. There are 17 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283009.2. 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
	RTEL1	NM_001283009.2	MANE Select	c.2775C>T	p.Ser925Ser	synonymous	Exon 29 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2847C>T	p.Ser949Ser	synonymous	Exon 29 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2775C>T	p.Ser925Ser	synonymous	Exon 29 of 35	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2775C>T	p.Ser925Ser	synonymous	Exon 29 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2847C>T	p.Ser949Ser	synonymous	Exon 29 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2775C>T	p.Ser925Ser	synonymous	Exon 29 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152208 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00835 AC: 2087 AN: 249842 AF XY: 0.00650

Gnomad AFR exome AF: 0.000621

Gnomad AMR exome AF: 0.0514

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00590

GnomAD4 exome AF: 0.00241 AC: 3519 AN: 1460326 Hom.: 90 Cov.: 31 AF XY: 0.00221 AC XY: 1603 AN XY: 726456

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.0504 AC: 2254 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 AN: 26128

East Asian (EAS) AF: 0.00516 AC: 205 AN: 39700

South Asian (SAS) AF: 0.00226 AC: 195 AN: 86258

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52082

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.000507 AC: 564 AN: 1111844

Other (OTH) AF: 0.00265 AC: 160 AN: 60360

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152326 Hom.: 17 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74492

African (AFR) AF: 0.000722 AC: 30 AN: 41572

American (AMR) AF: 0.0341 AC: 522 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5184

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00705

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.072
DANN	Benign	0.79
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12480346; hg19: chr20-62324280; COSMIC: COSV58894644; COSMIC: COSV58894644;