20-63694435-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1019E) 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 criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.676

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

Verdict is Benign. Variant got -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]. Clinvar id is 436577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63694435-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.3056A>G	p.Gln1019Arg	missense_variant	31/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.3883A>G		non_coding_transcript_exon_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.3056A>G	p.Gln1019Arg	missense_variant	31/35	5	NM_001283009.2	A2

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

GnomAD3 exomes AF: 0.000996 AC: 246 AN: 246902 Hom.: 4 AF XY: 0.000759 AC XY: 102 AN XY: 134410

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00995

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000812

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

Gnomad4 AFR AF: 0.00950

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00189

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

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
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;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.4	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.40	N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.36	T;T;T;.
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.094
MVP		0.38
ClinPred		0.00090	T
GERP RS		1.8
Varity_R		0.024
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs116053476; hg19: chr20-62325788;