rs115303435

Variant names:

• chr20-63694806-G-A
• rs115303435
• NM_001283009.2:c.3175G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63694806-G-A
• chr20-63694806-G-T

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.3175G>A​(p.Ala1059Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,612,396 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1059S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.324
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028603077).
• BP6: Variant 20-63694806-G-A is Benign according to our data. Variant chr20-63694806-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00157 (239/152352) while in subpopulation EAS AF = 0.0367 (190/5174). AF 95% confidence interval is 0.0325. There are 5 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.3175G>A	p.Ala1059Thr	missense	Exon 32 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.3247G>A	p.Ala1083Thr	missense	Exon 32 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.3175G>A	p.Ala1059Thr	missense	Exon 32 of 35	NP_057518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.3175G>A	p.Ala1059Thr	missense	Exon 32 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.3247G>A	p.Ala1083Thr	missense	Exon 32 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.3175G>A	p.Ala1059Thr	missense	Exon 32 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152234 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0368

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00318 AC: 790 AN: 248088 AF XY: 0.00293

Gnomad AFR exome AF: 0.000757

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0398

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00141 AC: 2062 AN: 1460044 Hom.: 32 Cov.: 35 AF XY: 0.00137 AC XY: 995 AN XY: 726326

African (AFR) AF: 0.000359 AC: 12 AN: 33472

American (AMR) AF: 0.0000895 AC: 4 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0444 AC: 1764 AN: 39694

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111730

Other (OTH) AF: 0.00260 AC: 157 AN: 60350

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74498

African (AFR) AF: 0.000505 AC: 21 AN: 41588

American (AMR) AF: 0.000718 AC: 11 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.00172

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000461 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00301 AC: 361

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (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	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.32
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.21	T
Polyphen		0.18	B
Vest4		0.091
MVP		0.42
ClinPred		0.00041	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.041
gMVP		0.28
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115303435; hg19: chr20-62326159; COSMIC: COSV99422698; COSMIC: COSV99422698;