rs61736615

Variant names:

• chr20-63692937-G-A
• rs61736615
• NM_001283009.2:c.2785G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63692937-G-A
• chr20-63692937-G-C

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.2785G>A​(p.Ala929Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,612,586 control chromosomes in the GnomAD database, including 1,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A929G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (57 hom., cov: 33)
  • Exomes 𝑓: 0.034 (950 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.375
• Publications: 12 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=0.002790749).
• BP6: Variant 20-63692937-G-A is Benign according to our data. Variant chr20-63692937-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.026 (3956/152306) while in subpopulation NFE AF = 0.0376 (2558/68004). AF 95% confidence interval is 0.0364. There are 57 homozygotes in GnomAd4. There are 1883 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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.2785G>A	p.Ala929Thr	missense	Exon 29 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.2857G>A	p.Ala953Thr	missense	Exon 29 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.2785G>A	p.Ala929Thr	missense	Exon 29 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.2785G>A	p.Ala929Thr	missense	Exon 29 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.2857G>A	p.Ala953Thr	missense	Exon 29 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.2785G>A	p.Ala929Thr	missense	Exon 29 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3956 AN: 152188 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00951

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0274 AC: 6839 AN: 249762 AF XY: 0.0284

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0341 AC: 49732 AN: 1460280 Hom.: 950 Cov.: 33 AF XY: 0.0339 AC XY: 24660 AN XY: 726438

African (AFR) AF: 0.00606 AC: 203 AN: 33480

American (AMR) AF: 0.0201 AC: 898 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 665 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0130 AC: 1120 AN: 86256

European-Finnish (FIN) AF: 0.0378 AC: 1969 AN: 52082

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5766

European-Non Finnish (NFE) AF: 0.0386 AC: 42865 AN: 1111800

Other (OTH) AF: 0.0315 AC: 1904 AN: 60360

GnomAD4 genome AF: 0.0260 AC: 3956 AN: 152306 Hom.: 57 Cov.: 33 AF XY: 0.0253 AC XY: 1883 AN XY: 74466

African (AFR) AF: 0.00828 AC: 344 AN: 41570

American (AMR) AF: 0.0286 AC: 438 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4832

European-Finnish (FIN) AF: 0.0360 AC: 382 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2558 AN: 68004

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0285 Hom.: 49

Bravo AF: 0.0252

TwinsUK AF: 0.0396 AC: 147

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0370 AC: 318

ExAC AF: 0.0271 AC: 3273

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0375

EpiControl AF: 0.0419

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.38
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.023
Sift	Benign	0.095	T
Sift4G	Benign	0.25	T
Polyphen		0.21	B
Vest4		0.076
ClinPred		0.0023	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.16
Mutation Taster		=97/3	polymorphism (auto)

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: rs61736615; hg19: chr20-62324290; COSMIC: COSV58898629; COSMIC: COSV58898629;