NM_001283009.2:c.3590G>C

Variant names:

• chr20-63695418-G-C
• rs138500086
• NM_001283009.2:c.3590G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):​c.3590G>C​(p.Gly1197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,562,816 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1197S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.665
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005782455).

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.3590G>C	p.Gly1197Ala	missense	Exon 34 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3662G>C	p.Gly1221Ala	missense	Exon 34 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3590G>C	p.Gly1197Ala	missense	Exon 34 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.3590G>C	p.Gly1197Ala	missense	Exon 34 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3662G>C	p.Gly1221Ala	missense	Exon 34 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3590G>C	p.Gly1197Ala	missense	Exon 34 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000173 AC: 36 AN: 207938 AF XY: 0.000117

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.000336

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000403

GnomAD4 exome AF: 0.0000907 AC: 128 AN: 1410500 Hom.: 1 Cov.: 34 AF XY: 0.0000820 AC XY: 57 AN XY: 695518

African (AFR) AF: 0.00 AC: 0 AN: 32388

American (AMR) AF: 0.000926 AC: 37 AN: 39954

Ashkenazi Jewish (ASJ) AF: 0.000535 AC: 12 AN: 22436

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49632

Middle Eastern (MID) AF: 0.000363 AC: 2 AN: 5508

European-Non Finnish (NFE) AF: 0.0000507 AC: 55 AN: 1085414

Other (OTH) AF: 0.000361 AC: 21 AN: 58154

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74478

African (AFR) AF: 0.0000962 AC: 4 AN: 41576

American (AMR) AF: 0.00255 AC: 39 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000631

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000192 AC: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.90
DANN	Benign	0.65
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.67
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.52
ClinPred		0.0088	T
GERP RS		-0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.036
gMVP		0.23
Mutation Taster		=100/0	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: rs138500086; hg19: chr20-62326771;