chr20-63693189-G-C

Variant names:

• chr20-63693189-G-C
• rs115464632
• NM_001283009.2:c.2898G>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.2898G>C​(p.Glu966Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,612,174 control chromosomes in the GnomAD database, including 12 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. E966K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (5 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.660
• Publications: 3 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=0.0036059618).
• BP6: Variant 20-63693189-G-C is Benign according to our data. Variant chr20-63693189-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436574.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 = 0.00528 (804/152188) while in subpopulation AFR AF = 0.0185 (766/41504). AF 95% confidence interval is 0.0174. There are 7 homozygotes in GnomAd4. There are 373 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.2898G>C	p.Glu966Asp	missense	Exon 30 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2970G>C	p.Glu990Asp	missense	Exon 30 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2898G>C	p.Glu966Asp	missense	Exon 30 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.2898G>C	p.Glu966Asp	missense	Exon 30 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2970G>C	p.Glu990Asp	missense	Exon 30 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2898G>C	p.Glu966Asp	missense	Exon 30 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 801 AN: 152070 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00142 AC: 355 AN: 249374 AF XY: 0.000938

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000540 AC: 789 AN: 1459986 Hom.: 5 Cov.: 33 AF XY: 0.000457 AC XY: 332 AN XY: 726290

African (AFR) AF: 0.0199 AC: 667 AN: 33474

American (AMR) AF: 0.000716 AC: 32 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111582

Other (OTH) AF: 0.000895 AC: 54 AN: 60338

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152188 Hom.: 7 Cov.: 33 AF XY: 0.00501 AC XY: 373 AN XY: 74408

African (AFR) AF: 0.0185 AC: 766 AN: 41504

American (AMR) AF: 0.00177 AC: 27 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67966

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.00604

ESP6500AA AF: 0.0198 AC: 87

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00170 AC: 205

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.10	N
PhyloP100		0.66
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.091
Sift	Benign	0.50	T
Sift4G	Benign	0.17	T
Polyphen		0.0050	B
Vest4		0.33
MutPred		0.30		Gain of sheet (P = 0.0477)
MVP		0.34
ClinPred		0.013	T
GERP RS		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.32
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: rs115464632; hg19: chr20-62324542;