20-63691785-C-T

Variant names:

• chr20-63691785-C-T
• rs139083375
• NM_001283009.2:c.2600C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001283009.2(RTEL1):​c.2600C>T​(p.Pro867Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,612,468 control chromosomes in the GnomAD database, including 3 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. P867A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (3 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 0.143
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005922228).
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2600C>T	p.Pro867Leu	missense	Exon 28 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2672C>T	p.Pro891Leu	missense	Exon 28 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2600C>T	p.Pro867Leu	missense	Exon 28 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.2600C>T	p.Pro867Leu	missense	Exon 28 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2672C>T	p.Pro891Leu	missense	Exon 28 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2600C>T	p.Pro867Leu	missense	Exon 28 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00113

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000450 AC: 112 AN: 248858 AF XY: 0.000459

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000780

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000734 AC: 1072 AN: 1460240 Hom.: 3 Cov.: 31 AF XY: 0.000749 AC XY: 544 AN XY: 726416

African (AFR) AF: 0.000448 AC: 15 AN: 33476

American (AMR) AF: 0.000425 AC: 19 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51998

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000879 AC: 977 AN: 1111836

Other (OTH) AF: 0.000961 AC: 58 AN: 60366

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74402

African (AFR) AF: 0.000361 AC: 15 AN: 41552

American (AMR) AF: 0.000327 AC: 5 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 67996

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000431 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.4
DANN	Benign	0.69
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.14
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.010
Sift	Benign	0.72	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.092
MVP		0.082
ClinPred		0.0011	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.17
Mutation Taster		=94/6	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: rs139083375; hg19: chr20-62323138; COSMIC: COSV100542854; COSMIC: COSV100542854;