20-63688532-G-A

Variant names:

• chr20-63688532-G-A
• rs115423936
• NM_001283009.2:c.1727G>A

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.1727G>A​(p.Arg576His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,610,342 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R576C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (5 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.582
• Publications: 5 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=0.0044119954).
• BP6: Variant 20-63688532-G-A is Benign according to our data. Variant chr20-63688532-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00523 (797/152304) while in subpopulation AFR AF = 0.0185 (767/41542). AF 95% confidence interval is 0.0174. There are 7 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1727G>A	p.Arg576His	missense	Exon 21 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1799G>A	p.Arg600His	missense	Exon 21 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.1727G>A	p.Arg576His	missense	Exon 21 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.1727G>A	p.Arg576His	missense	Exon 21 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1799G>A	p.Arg600His	missense	Exon 21 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.1727G>A	p.Arg576His	missense	Exon 21 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 792 AN: 152186 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00123 AC: 300 AN: 243708 AF XY: 0.000896

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.000508 AC: 740 AN: 1458038 Hom.: 5 Cov.: 32 AF XY: 0.000411 AC XY: 298 AN XY: 725296

African (AFR) AF: 0.0188 AC: 630 AN: 33454

American (AMR) AF: 0.000585 AC: 26 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51326

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5500

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111458

Other (OTH) AF: 0.000930 AC: 56 AN: 60226

GnomAD4 genome AF: 0.00523 AC: 797 AN: 152304 Hom.: 7 Cov.: 33 AF XY: 0.00463 AC XY: 345 AN XY: 74476

African (AFR) AF: 0.0185 AC: 767 AN: 41542

American (AMR) AF: 0.00157 AC: 24 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00281 Hom.: 5

Bravo AF: 0.00595

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0183 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00158 AC: 190

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.64
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.58
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.27
Sift	Benign	0.55	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.14
MVP		0.62
ClinPred		0.0078	T
GERP RS		-3.9
PromoterAI		0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.39
Mutation Taster		=99/1	polymorphism

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: rs115423936; hg19: chr20-62319885; COSMIC: COSV58892013; COSMIC: COSV58892013;