chr20-63678161-G-A

Variant names:

• chr20-63678161-G-A
• rs41302954
• NM_001283009.2:c.936G>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.936G>A​(p.Leu312Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,118 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L312L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 29)
  • Exomes 𝑓: 0.012 (122 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0230
• Publications: 6 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=-0.57).
• BP6: Variant 20-63678161-G-A is Benign according to our data. Variant chr20-63678161-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00947 (1442/152316) while in subpopulation NFE AF = 0.0144 (982/68024). AF 95% confidence interval is 0.0137. There are 11 homozygotes in GnomAd4. There are 710 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.936G>A	p.Leu312Leu	synonymous	Exon 11 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1008G>A	p.Leu336Leu	synonymous	Exon 11 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.936G>A	p.Leu312Leu	synonymous	Exon 11 of 35	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.936G>A	p.Leu312Leu	synonymous	Exon 11 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1008G>A	p.Leu336Leu	synonymous	Exon 11 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.936G>A	p.Leu312Leu	synonymous	Exon 11 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.00947 AC: 1442 AN: 152198 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0101 AC: 2527 AN: 251278 AF XY: 0.0102

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0117 AC: 17066 AN: 1461802 Hom.: 122 Cov.: 31 AF XY: 0.0116 AC XY: 8469 AN XY: 727196

African (AFR) AF: 0.00188 AC: 63 AN: 33478

American (AMR) AF: 0.00499 AC: 223 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 712 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00894 AC: 771 AN: 86254

European-Finnish (FIN) AF: 0.0125 AC: 666 AN: 53400

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13835 AN: 1111958

Other (OTH) AF: 0.0121 AC: 729 AN: 60394

GnomAD4 genome AF: 0.00947 AC: 1442 AN: 152316 Hom.: 11 Cov.: 29 AF XY: 0.00953 AC XY: 710 AN XY: 74476

African (AFR) AF: 0.00180 AC: 75 AN: 41572

American (AMR) AF: 0.00386 AC: 59 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4826

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 982 AN: 68024

Other (OTH) AF: 0.0157 AC: 33 AN: 2106

Alfa AF: 0.0129 Hom.: 34

Bravo AF: 0.00825

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.7
DANN	Benign	0.85
PhyloP100		-0.023
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41302954; hg19: chr20-62309514;