rs3208008

Variant names:

• chr20-63694757-A-C
• rs3208008
• NM_001283009.2:c.3126A>C
• RTEL1 p.Gln1042His

Your query was ambiguous. Multiple possible variants found:

• chr20-63694757-A-C
• chr20-63694757-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001283009.2(RTEL1):​c.3126A>C​(p.Gln1042His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,603,768 control chromosomes in the GnomAD database, including 465,486 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1042Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (50454 hom., cov: 34)
  • Exomes 𝑓: 0.75 (415032 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.643
• Publications: 54 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=9.625584E-7).
• BP6: Variant 20-63694757-A-C is Benign according to our data. Variant chr20-63694757-A-C is described in ClinVar as Benign. ClinVar VariationId is 403402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

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.3126A>C	p.Gln1042His	missense	Exon 32 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3198A>C	p.Gln1066His	missense	Exon 32 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3126A>C	p.Gln1042His	missense	Exon 32 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.3126A>C	p.Gln1042His	missense	Exon 32 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3198A>C	p.Gln1066His	missense	Exon 32 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3126A>C	p.Gln1042His	missense	Exon 32 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122554 AN: 152106 Hom.: 50397 Cov.: 34

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.802

GnomAD2 exomes AF: 0.748 AC: 181757 AN: 242878 AF XY: 0.749

Gnomad AFR exome AF: 0.943

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.357

Gnomad FIN exome AF: 0.801

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.752 AC: 1091745 AN: 1451544 Hom.: 415032 Cov.: 51 AF XY: 0.752 AC XY: 542105 AN XY: 720928

African (AFR) AF: 0.949 AC: 31547 AN: 33234

American (AMR) AF: 0.752 AC: 33151 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 20039 AN: 25958

East Asian (EAS) AF: 0.378 AC: 14905 AN: 39440

South Asian (SAS) AF: 0.745 AC: 64083 AN: 86024

European-Finnish (FIN) AF: 0.800 AC: 40325 AN: 50410

Middle Eastern (MID) AF: 0.799 AC: 4580 AN: 5730

European-Non Finnish (NFE) AF: 0.757 AC: 838223 AN: 1106718

Other (OTH) AF: 0.749 AC: 44892 AN: 59926

GnomAD4 genome AF: 0.806 AC: 122673 AN: 152224 Hom.: 50454 Cov.: 34 AF XY: 0.804 AC XY: 59794 AN XY: 74408

African (AFR) AF: 0.938 AC: 38986 AN: 41580

American (AMR) AF: 0.788 AC: 12058 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2668 AN: 3468

East Asian (EAS) AF: 0.371 AC: 1909 AN: 5148

South Asian (SAS) AF: 0.737 AC: 3553 AN: 4824

European-Finnish (FIN) AF: 0.799 AC: 8470 AN: 10604

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52403 AN: 67982

Other (OTH) AF: 0.798 AC: 1689 AN: 2116

Alfa AF: 0.768 Hom.: 60863

Bravo AF: 0.807

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (5)
-	-	1	Dyskeratosis congenita (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5 (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)
-	-	1	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.50
DANN	Benign	0.57
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.024	T
MetaRNN	Benign	9.6e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.64
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.17
Sift	Benign	0.25	T
Sift4G	Benign	0.17	T
Varity_R		0.067
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3208008;

hg19: chr20-62326110;

COSMIC: COSV53926243;

COSMIC: COSV53926243;