NM_001283009.2:c.2051G>A

Variant names:

• chr20-63689775-G-A
• rs35640778
• NM_001283009.2:c.2051G>A

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.2051G>A​(p.Arg684Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,612,098 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R684W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 33)
  • Exomes 𝑓: 0.018 (287 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.02
• Publications: 23 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=0.0063221157).
• BP6: Variant 20-63689775-G-A is Benign according to our data. Variant chr20-63689775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1786/152264) while in subpopulation NFE AF = 0.0182 (1236/67998). AF 95% confidence interval is 0.0173. There are 14 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.2051G>A	p.Arg684Gln	missense	Exon 24 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2123G>A	p.Arg708Gln	missense	Exon 24 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2051G>A	p.Arg684Gln	missense	Exon 24 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.2051G>A	p.Arg684Gln	missense	Exon 24 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2123G>A	p.Arg708Gln	missense	Exon 24 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2051G>A	p.Arg684Gln	missense	Exon 24 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1786 AN: 152148 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0123 AC: 3046 AN: 247198 AF XY: 0.0133

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.00404

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0178 AC: 26007 AN: 1459834 Hom.: 287 Cov.: 35 AF XY: 0.0178 AC XY: 12893 AN XY: 726258

African (AFR) AF: 0.00215 AC: 72 AN: 33476

American (AMR) AF: 0.00523 AC: 234 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26114

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0127 AC: 1097 AN: 86252

European-Finnish (FIN) AF: 0.0139 AC: 720 AN: 51792

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5764

European-Non Finnish (NFE) AF: 0.0204 AC: 22724 AN: 1111698

Other (OTH) AF: 0.0156 AC: 942 AN: 60340

GnomAD4 genome AF: 0.0117 AC: 1786 AN: 152264 Hom.: 14 Cov.: 33 AF XY: 0.0112 AC XY: 832 AN XY: 74444

African (AFR) AF: 0.00325 AC: 135 AN: 41562

American (AMR) AF: 0.00784 AC: 120 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.0178 AC: 189 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1236 AN: 67998

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0141 Hom.: 10

Bravo AF: 0.0107

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00319 AC: 14

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0129 AC: 1552

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0192

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (2)
-	-	2	not specified (2)
-	-	1	Dyskeratosis congenita (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.77	N
PhyloP100		2.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.77	T
Sift4G	Benign	0.46	T
Polyphen		0.18	B
Vest4		0.12
ClinPred		0.0070	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.39
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35640778; hg19: chr20-62321128;