rs115610405

Variant names:

• chr20-63694480-C-A
• rs115610405
• NM_001283009.2:c.3101C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63694480-C-A
• chr20-63694480-C-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.3101C>A​(p.Pro1034His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,597,222 control chromosomes in the GnomAD database, including 342 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P1034S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (43 hom., cov: 31)
  • Exomes 𝑓: 0.018 (299 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.196
• Publications: 11 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=0.0027760863).
• BP6: Variant 20-63694480-C-A is Benign according to our data. Variant chr20-63694480-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473917.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 = 0.0158 (2402/152326) while in subpopulation NFE AF = 0.0201 (1367/68028). AF 95% confidence interval is 0.0192. There are 43 homozygotes in GnomAd4. There are 1222 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.3101C>A	p.Pro1034His	missense	Exon 31 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3173C>A	p.Pro1058His	missense	Exon 31 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3101C>A	p.Pro1034His	missense	Exon 31 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.3101C>A	p.Pro1034His	missense	Exon 31 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3173C>A	p.Pro1058His	missense	Exon 31 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3101C>A	p.Pro1034His	missense	Exon 31 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2401 AN: 152208 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0161 AC: 3944 AN: 244392 AF XY: 0.0163

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.00688

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0182 AC: 26335 AN: 1444896 Hom.: 299 Cov.: 32 AF XY: 0.0178 AC XY: 12761 AN XY: 715800

African (AFR) AF: 0.00280 AC: 93 AN: 33166

American (AMR) AF: 0.00908 AC: 401 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00711 AC: 184 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.000793 AC: 68 AN: 85774

European-Finnish (FIN) AF: 0.0461 AC: 2395 AN: 51916

Middle Eastern (MID) AF: 0.00350 AC: 20 AN: 5710

European-Non Finnish (NFE) AF: 0.0202 AC: 22177 AN: 1099448

Other (OTH) AF: 0.0167 AC: 997 AN: 59620

GnomAD4 genome AF: 0.0158 AC: 2402 AN: 152326 Hom.: 43 Cov.: 31 AF XY: 0.0164 AC XY: 1222 AN XY: 74482

African (AFR) AF: 0.00414 AC: 172 AN: 41580

American (AMR) AF: 0.0144 AC: 220 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

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

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.0517 AC: 549 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0201 AC: 1367 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0185 Hom.: 69

Bravo AF: 0.0131

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00574 AC: 25

ESP6500EA AF: 0.0191 AC: 163

ExAC AF: 0.0159 AC: 1911

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0202

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.20
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.40	T
Sift4G	Benign	0.35	T
Polyphen		0.94	P
Vest4		0.26
ClinPred		0.0065	T
GERP RS		-0.64
Varity_R		0.080
gMVP		0.23
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: rs115610405; hg19: chr20-62325833;