rs148621466

Variant names:

• chr20-63694960-T-A
• rs148621466
• NM_001283009.2:c.3329T>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63694960-T-A
• chr20-63694960-T-C

Variant summary

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

The NM_001283009.2(RTEL1):​c.3329T>A​(p.Phe1110Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,612,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1110V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.341
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24929056).

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.3329T>A	p.Phe1110Tyr	missense	Exon 32 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3401T>A	p.Phe1134Tyr	missense	Exon 32 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3329T>A	p.Phe1110Tyr	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.3329T>A	p.Phe1110Tyr	missense	Exon 32 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3401T>A	p.Phe1134Tyr	missense	Exon 32 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3329T>A	p.Phe1110Tyr	missense	Exon 32 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151920 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 244346 AF XY: 0.0000150

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460140 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 726350

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51954

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111810

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151920 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

African (AFR) AF: 0.0000242 AC: 1 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000457 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000250 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (2)
-	2	-	not provided (2)
-	1	-	Dyskeratosis congenita (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.074
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.34
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T
Sift4G	Uncertain	0.027	D
Polyphen		0.76	P
Vest4		0.29
MVP		0.70
ClinPred		0.43	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.34
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148621466; hg19: chr20-62326313;