20-63694435-A-G

Variant names:

• chr20-63694435-A-G
• rs116053476
• NM_001283009.2:c.3056A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001283009.2(RTEL1):​c.3056A>G​(p.Gln1019Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,611,978 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1019L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.676
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026519).
• BP6: Variant 20-63694435-A-G is Benign according to our data. Variant chr20-63694435-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00294 (447/152046) while in subpopulation AFR AF = 0.0095 (394/41452). AF 95% confidence interval is 0.00873. There are 2 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.3056A>G	p.Gln1019Arg	missense	Exon 31 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.3128A>G	p.Gln1043Arg	missense	Exon 31 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.3056A>G	p.Gln1019Arg	missense	Exon 31 of 35	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.3056A>G	p.Gln1019Arg	missense	Exon 31 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.3128A>G	p.Gln1043Arg	missense	Exon 31 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.3056A>G	p.Gln1019Arg	missense	Exon 31 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 151928 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00958

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000996 AC: 246 AN: 246902 AF XY: 0.000759

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000438 AC: 640 AN: 1459932 Hom.: 5 Cov.: 33 AF XY: 0.000413 AC XY: 300 AN XY: 726170

African (AFR) AF: 0.00995 AC: 333 AN: 33474

American (AMR) AF: 0.000962 AC: 43 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52072

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1111526

Other (OTH) AF: 0.000812 AC: 49 AN: 60344

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152046 Hom.: 2 Cov.: 31 AF XY: 0.00276 AC XY: 205 AN XY: 74344

African (AFR) AF: 0.00950 AC: 394 AN: 41452

American (AMR) AF: 0.00203 AC: 31 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67958

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00161 Hom.: 2

Bravo AF: 0.00366

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00127 AC: 152

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTEL1: BP4, BS1, BS2

Feb 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jun 23, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.3
DANN	Benign	0.85
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.0087	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.68
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.15
Sift	Benign	0.36	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.38
ClinPred		0.00090	T
GERP RS		1.8
Varity_R		0.024
gMVP		0.21
Mutation Taster		=99/1	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: rs116053476; hg19: chr20-62325788;