20-63678280-G-A

Variant names:

• chr20-63678280-G-A
• rs113684274
• NM_001283009.2:c.971G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001283009.2(RTEL1):​c.971G>A​(p.Arg324His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,612,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 2.71
• Publications: 1 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]

LOC124904954 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09220213).

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.971G>A	p.Arg324His	missense	Exon 12 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1043G>A	p.Arg348His	missense	Exon 12 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.971G>A	p.Arg324His	missense	Exon 12 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.971G>A	p.Arg324His	missense	Exon 12 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1043G>A	p.Arg348His	missense	Exon 12 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.971G>A	p.Arg324His	missense	Exon 12 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000212 AC: 53 AN: 249636 AF XY: 0.000155

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1460312 Hom.: 0 Cov.: 36 AF XY: 0.000343 AC XY: 249 AN XY: 726230

African (AFR) AF: 0.00123 AC: 41 AN: 33464

American (AMR) AF: 0.000134 AC: 6 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26086

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86142

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53098

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000351 AC: 390 AN: 1111148

Other (OTH) AF: 0.000348 AC: 21 AN: 60326

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74424

African (AFR) AF: 0.00104 AC: 43 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000570

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Dyskeratosis congenita (2)
-	2	-	Dyskeratosis congenita, autosomal recessive 5 (2)
-	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	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.18
Sift	Benign	0.074	T
Sift4G	Benign	0.071	T
Polyphen		0.068	B
Vest4		0.33
MVP		0.81
ClinPred		0.020	T
GERP RS		0.69
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.042
gMVP		0.21
Mutation Taster		=95/5	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: rs113684274; hg19: chr20-62309633;