rs41310197

Variant names:

• chr20-63678287-G-A
• rs41310197
• NM_001283009.2:c.978G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001283009.2(RTEL1):​c.978G>A​(p.Glu326Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,612,566 control chromosomes in the GnomAD database, including 1,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (88 hom., cov: 31)
  • Exomes 𝑓: 0.036 (1056 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.60
• Publications: 7 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]

LOC124904954 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 20-63678287-G-A is Benign according to our data. Variant chr20-63678287-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4296/152214) while in subpopulation NFE AF = 0.0406 (2762/67994). AF 95% confidence interval is 0.0394. There are 88 homozygotes in GnomAd4. There are 2123 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 88 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTEL1	NM_001283009.2	c.978G>A	p.Glu326Glu	synonymous_variant	Exon 12 of 35	ENST00000360203.11	NP_001269938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTEL1	ENST00000360203.11	c.978G>A	p.Glu326Glu	synonymous_variant	Exon 12 of 35	5	NM_001283009.2	ENSP00000353332.5
RTEL1	ENST00000508582.7	c.1050G>A	p.Glu350Glu	synonymous_variant	Exon 12 of 35	2		ENSP00000424307.2
RTEL1	ENST00000370018.7	c.978G>A	p.Glu326Glu	synonymous_variant	Exon 12 of 35	1		ENSP00000359035.3
RTEL1-TNFRSF6B	ENST00000492259.6	n.1062G>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000457428.1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4295 AN: 152096 Hom.: 87 Cov.: 31

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0280 AC: 6986 AN: 249554 AF XY: 0.0281

Gnomad AFR exome AF: 0.00616

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.00552

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0296

GnomAD4 exome AF: 0.0362 AC: 52927 AN: 1460352 Hom.: 1056 Cov.: 36 AF XY: 0.0354 AC XY: 25674 AN XY: 726248

African (AFR) AF: 0.00613 AC: 205 AN: 33466

American (AMR) AF: 0.0230 AC: 1027 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00644 AC: 168 AN: 26082

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39666

South Asian (SAS) AF: 0.0117 AC: 1005 AN: 86126

European-Finnish (FIN) AF: 0.0479 AC: 2540 AN: 53076

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5760

European-Non Finnish (NFE) AF: 0.0414 AC: 45951 AN: 1111218

Other (OTH) AF: 0.0325 AC: 1959 AN: 60322

GnomAD4 genome AF: 0.0282 AC: 4296 AN: 152214 Hom.: 88 Cov.: 31 AF XY: 0.0285 AC XY: 2123 AN XY: 74418

African (AFR) AF: 0.00727 AC: 302 AN: 41536

American (AMR) AF: 0.0325 AC: 497 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00995 AC: 48 AN: 4822

European-Finnish (FIN) AF: 0.0539 AC: 572 AN: 10606

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0406 AC: 2762 AN: 67994

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0339 Hom.: 181

Bravo AF: 0.0252

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0369

EpiControl AF: 0.0372

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.4
DANN	Benign	0.67
PhyloP100		1.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41310197; hg19: chr20-62309640; COSMIC: COSV58898822; COSMIC: COSV58898822;