rs143550996

chr20-63678268-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

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. 16/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. M320V) has been classified as Uncertain significance.

• 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:4 B:2
• Conservation: PhyloP100: 0.568

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:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013461858).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.959T>C	p.Met320Thr	missense_variant, splice_region_variant	12/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152042 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.00113 AC XY: 153 AN XY: 135286

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.: 4 Cov.: 36 AF XY: 0.00154 AC XY: 1115 AN XY: 726126

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.: 0 Cov.: 31 AF XY: 0.00116 AC XY: 86 AN XY: 74388

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.: 1

Bravo AF: 0.000907

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	- -
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) -

Dyskeratosis congenita Uncertain:1 Benign:1

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

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
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	D
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs143550996; hg19: chr20-62309621;