chr20-63695134-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001283009.2(RTEL1):c.3412C>T(p.Arg1138Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,612,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. R1138Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001283009.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RTEL1 | ENST00000360203.11 | c.3412C>T | p.Arg1138Trp | missense_variant | Exon 33 of 35 | 5 | NM_001283009.2 | ENSP00000353332.5 | ||
RTEL1 | ENST00000508582.7 | c.3484C>T | p.Arg1162Trp | missense_variant | Exon 33 of 35 | 2 | ENSP00000424307.2 | |||
RTEL1 | ENST00000370018.7 | c.3412C>T | p.Arg1138Trp | missense_variant | Exon 33 of 35 | 1 | ENSP00000359035.3 | |||
RTEL1-TNFRSF6B | ENST00000492259.6 | n.*1014C>T | non_coding_transcript_exon_variant | Exon 30 of 35 | 5 | ENSP00000457428.1 | ||||
RTEL1-TNFRSF6B | ENST00000492259.6 | n.*1014C>T | 3_prime_UTR_variant | Exon 30 of 35 | 5 | ENSP00000457428.1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000857 AC: 21AN: 245096Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133604
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1460116Hom.: 0 Cov.: 35 AF XY: 0.0000399 AC XY: 29AN XY: 726350
GnomAD4 genome AF: 0.000236 AC: 36AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74454
ClinVar
Submissions by phenotype
Dyskeratosis congenita, autosomal recessive 5 Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1138 of the RTEL1 protein (p.Arg1138Trp). This variant is present in population databases (rs6062495, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 654387). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
RTEL1-related disorder Uncertain:1
The RTEL1 c.3484C>T variant is predicted to result in the amino acid substitution p.Arg1162Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.098% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Dyskeratosis congenita Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at