rs150461578

Variant names:

• chr20-63690835-G-T
• rs150461578
• NM_001283009.2:c.2444G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001283009.2(RTEL1):​c.2444G>T​(p.Ser815Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,605,996 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S815G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.958
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042290688).
• BP6: Variant 20-63690835-G-T is Benign according to our data. Variant chr20-63690835-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540960.
• 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.2444G>T	p.Ser815Ile	missense	Exon 27 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2516G>T	p.Ser839Ile	missense	Exon 27 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2444G>T	p.Ser815Ile	missense	Exon 27 of 35	NP_057518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2444G>T	p.Ser815Ile	missense	Exon 27 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2516G>T	p.Ser839Ile	missense	Exon 27 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2444G>T	p.Ser815Ile	missense	Exon 27 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152098 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00165 AC: 393 AN: 237664 AF XY: 0.00166

Gnomad AFR exome AF: 0.000275

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.000416

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00652

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00171 AC: 2482 AN: 1453780 Hom.: 7 Cov.: 31 AF XY: 0.00169 AC XY: 1220 AN XY: 722742

African (AFR) AF: 0.000390 AC: 13 AN: 33342

American (AMR) AF: 0.00159 AC: 70 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.000541 AC: 14 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85234

European-Finnish (FIN) AF: 0.00689 AC: 354 AN: 51416

Middle Eastern (MID) AF: 0.00165 AC: 7 AN: 4230

European-Non Finnish (NFE) AF: 0.00175 AC: 1939 AN: 1109998

Other (OTH) AF: 0.00140 AC: 84 AN: 59946

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152216 Hom.: 2 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74428

African (AFR) AF: 0.000385 AC: 16 AN: 41538

American (AMR) AF: 0.00144 AC: 22 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00230 AC: 156 AN: 67972

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00177 Hom.: 1

Bravo AF: 0.00152

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.000700 AC: 6

ExAC AF: 0.00119 AC: 143

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.96
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.047
Sift	Benign	0.037	D
Sift4G	Benign	0.072	T
Polyphen		0.075	B
Vest4		0.46
MVP		0.36
ClinPred		0.034	T
GERP RS		1.7
Varity_R		0.13
gMVP		0.41
Mutation Taster		=95/5	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: rs150461578; hg19: chr20-62322188;