NM_001283009.2:c.973C>T

Variant names:

• chr20-63678282-C-T
• rs142739953
• NM_001283009.2:c.973C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001283009.2(RTEL1):​c.973C>T​(p.Leu325Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,612,582 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: RTEL1 NM_001283009.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 2.45
• 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]

LOC124904954 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-63678282-C-T is Benign according to our data. Variant chr20-63678282-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,SD,AR 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.973C>T	p.Leu325Leu	synonymous	Exon 12 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.1045C>T	p.Leu349Leu	synonymous	Exon 12 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.973C>T	p.Leu325Leu	synonymous	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.973C>T	p.Leu325Leu	synonymous	Exon 12 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.1045C>T	p.Leu349Leu	synonymous	Exon 12 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.973C>T	p.Leu325Leu	synonymous	Exon 12 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000473 AC: 118 AN: 249676 AF XY: 0.000466

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000369 AC: 539 AN: 1460466 Hom.: 2 Cov.: 36 AF XY: 0.000391 AC XY: 284 AN XY: 726326

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000246 AC: 11 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.000753 AC: 40 AN: 53152

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000416 AC: 462 AN: 1111240

Other (OTH) AF: 0.000249 AC: 15 AN: 60314

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.000458 AC XY: 34 AN XY: 74304

African (AFR) AF: 0.0000483 AC: 2 AN: 41418

American (AMR) AF: 0.000327 AC: 5 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68008

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000871 Hom.: 0

Bravo AF: 0.000408

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Dyskeratosis congenita (1)
-	1	-	Dyskeratosis congenita, autosomal dominant 1 (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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.70
PhyloP100		2.4
Mutation Taster		=93/7	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: rs142739953; hg19: chr20-62309635;