chr20-63678268-T-C

Position:

chr20-63678268-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001283009.2(RTEL1):c.959T>C(p.Met320Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,612,424 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

RTEL1
NM_001283009.2 missense, splice_region

Scores

Splicing: ADA: 0.0001307

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.568

Variant links:

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 links:

RTEL1-TNFRSF6B (HGNC:):

RTEL1-TNFRSF6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013461858).

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RTEL1	NM_001283009.2 linkuse as main transcript	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	12/35	ENST00000360203.11	NP_001269938.1
RTEL1-TNFRSF6B	NR_037882.1 linkuse as main transcript	n.1786T>C		splice_region_variant, non_coding_transcript_exon_variant	12/38
LOC124904954	XR_007067717.1 linkuse as main transcript	n.108A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11 linkuse as main transcript	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	12/35	5	NM_001283009.2	ENSP00000353332	A2	Q9NZ71-6

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00112

AC:

279

AN:

249962

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000492

Gnomad FIN exome

AF:

0.00229

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00159

AC:

2317

AN:

1460264

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1115

AN XY:

726126

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00261

Gnomad4 NFE exome

AF:

0.00184

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152160

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00107

AC:

130

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	Identified in two individuals with suspected familial bone marrow failure, one with shortened telomeres that also carried a variant in TERT, and another with normal telomere length (Marsh 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as M320T (c.959T>C); This variant is associated with the following publications: (PMID: 29344583) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -

Dyskeratosis congenita

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 23, 2021	- -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 18, 2022

DNA sequence analysis of the RTEL1 gene demonstrated a sequence change, c.1031T>C, in exon 12 that results in an amino acid change, p.Met344Thr (cDNA transcript used: NM_032957.4). This sequence change has been described in the gnomAD database with a frequency of 0.22% in the European Finnish subpopulation (dbSNP rs143550996). The p.Met344Thr change affects a poorly conserved amino acid residue located in a domain of the RTEL1 protein that is known to be functional. The p.Met344Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with RTEL1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met344Thr change remains unknown at this time. -

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.7

DANN

Benign

0.35

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

L;.;L;.

MutationTaster

Benign

0.72

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.93

N;N;N;.

REVEL

Benign

0.20

Sift

Benign

0.54

T;T;T;.

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0060

B;B;B;.

Vest4

0.33

MVP

0.35

ClinPred

0.0069

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over