rs41297642

Variant names:

• chr20-63662509-C-T
• rs41297642
• ENST00000508582.7:c.431C>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_032957.5(RTEL1):​c.431C>T​(p.Thr144Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,611,504 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (12 hom.)
• Consequence: RTEL1 NM_032957.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0180
• Publications: 7 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=0.0065446794).
• BP6: Variant 20-63662509-C-T is Benign according to our data. Variant chr20-63662509-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436561.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 = 0.00299 (456/152338) while in subpopulation NFE AF = 0.00523 (356/68024). AF 95% confidence interval is 0.00478. There are 0 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032957.5. 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.396-37C>T		intron	N/A	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.431C>T	p.Thr144Ile	missense	Exon 5 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.396-37C>T		intron	N/A	NP_057518.1	Q9NZ71-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000508582.7	TSL:2	c.431C>T	p.Thr144Ile	missense	Exon 5 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000356810.5	TSL:1	c.509C>T	p.Thr170Ile	missense	Exon 5 of 10	ENSP00000349265.4	X6R5I7
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.396-37C>T		intron	N/A	ENSP00000353332.5	Q9NZ71-6

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00273 AC: 670 AN: 245238 AF XY: 0.00280

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.000650

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00136

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00394 AC: 5750 AN: 1459166 Hom.: 12 Cov.: 32 AF XY: 0.00384 AC XY: 2786 AN XY: 725628

African (AFR) AF: 0.00102 AC: 34 AN: 33470

American (AMR) AF: 0.000566 AC: 25 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26012

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85670

European-Finnish (FIN) AF: 0.00153 AC: 81 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00493 AC: 5474 AN: 1111090

Other (OTH) AF: 0.00222 AC: 134 AN: 60328

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74498

African (AFR) AF: 0.00120 AC: 50 AN: 41588

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00438 Hom.: 3

Bravo AF: 0.00267

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00288 AC: 350

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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)
-	-	1	Inborn genetic diseases (1)
-	-	1	RTEL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.1
DANN	Benign	0.81
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.79	T
PhyloP100		0.018
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.059
MVP		0.082
ClinPred		0.0051	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs41297642; hg19: chr20-62293862;