rs6062495

Variant names:

• chr20-63695134-C-A
• rs6062495
• NM_001283009.2:c.3412C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63695134-C-A
• chr20-63695134-C-G
• chr20-63695134-C-T

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.3412C>A​(p.Arg1138Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00887 in 1,612,400 control chromosomes in the GnomAD database, including 87 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. R1138R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (83 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.801
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 20-63695134-C-A is Benign according to our data. Variant chr20-63695134-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.801 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00582 (886/152288) while in subpopulation SAS AF = 0.0116 (56/4828). AF 95% confidence interval is 0.00917. There are 4 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3412C>A	p.Arg1138Arg	synonymous	Exon 33 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3484C>A	p.Arg1162Arg	synonymous	Exon 33 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3412C>A	p.Arg1138Arg	synonymous	Exon 33 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.3412C>A	p.Arg1138Arg	synonymous	Exon 33 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3484C>A	p.Arg1162Arg	synonymous	Exon 33 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3412C>A	p.Arg1138Arg	synonymous	Exon 33 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152170 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00953

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00726 AC: 1779 AN: 245096 AF XY: 0.00757

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00598

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00919 AC: 13421 AN: 1460112 Hom.: 83 Cov.: 35 AF XY: 0.00902 AC XY: 6555 AN XY: 726348

African (AFR) AF: 0.00116 AC: 39 AN: 33478

American (AMR) AF: 0.00186 AC: 83 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26128

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39698

South Asian (SAS) AF: 0.00834 AC: 719 AN: 86256

European-Finnish (FIN) AF: 0.00590 AC: 306 AN: 51866

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0106 AC: 11786 AN: 1111848

Other (OTH) AF: 0.00759 AC: 458 AN: 60356

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152288 Hom.: 4 Cov.: 33 AF XY: 0.00549 AC XY: 409 AN XY: 74454

African (AFR) AF: 0.00137 AC: 57 AN: 41560

American (AMR) AF: 0.00373 AC: 57 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4828

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00953 AC: 648 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00507 Hom.: 0

Bravo AF: 0.00531

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6062495; hg19: chr20-62326487;