NM_001283009.2:c.2662G>C

Variant names:

• chr20-63692814-G-C
• rs200505378
• NM_001283009.2:c.2662G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.2662G>C​(p.Val888Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,610,786 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V888M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.63
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00453043).
• BP6: Variant 20-63692814-G-C is Benign according to our data. Variant chr20-63692814-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 719059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000223 (34/152330) while in subpopulation SAS AF = 0.00662 (32/4832). AF 95% confidence interval is 0.00482. There are 2 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD 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.2662G>C	p.Val888Leu	missense	Exon 29 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2734G>C	p.Val912Leu	missense	Exon 29 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2662G>C	p.Val888Leu	missense	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.2662G>C	p.Val888Leu	missense	Exon 29 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2734G>C	p.Val912Leu	missense	Exon 29 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2662G>C	p.Val888Leu	missense	Exon 29 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152212 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000695 AC: 173 AN: 248776 AF XY: 0.000909

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000332 AC: 484 AN: 1458456 Hom.: 4 Cov.: 31 AF XY: 0.000479 AC XY: 347 AN XY: 725150

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00530 AC: 457 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110496

Other (OTH) AF: 0.000415 AC: 25 AN: 60242

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152330 Hom.: 2 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00662 AC: 32 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000706 AC: 85

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dyskeratosis congenita (2)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.5
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.042
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.037	B
Vest4		0.14
MutPred		0.53		Gain of glycosylation at P887 (P = 0.1137)
MVP		0.30
ClinPred		0.014	T
GERP RS		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.26
Mutation Taster		=95/5	polymorphism

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: rs200505378; hg19: chr20-62324167;