chr20-63678326-C-A

Position:

• chr20-63678326-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001283009.2(RTEL1):​c.1017C>A​(p.Ser339Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S339T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08751565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTEL1	NM_001283009.2	c.1017C>A	p.Ser339Arg	missense_variant	12/35	ENST00000360203.11
RTEL1-TNFRSF6B	NR_037882.1	n.1844C>A		non_coding_transcript_exon_variant	12/38
LOC124904954	XR_007067717.1	n.50G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTEL1	ENST00000360203.11	c.1017C>A	p.Ser339Arg	missense_variant	12/35	5	NM_001283009.2	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.0010
DANN	Benign	0.68
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.41	T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.66	T;T;T;.
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.19
MutPred		0.32		Loss of glycosylation at S339 (P = 0.0065);.;Loss of glycosylation at S339 (P = 0.0065);.;
MVP		0.55
ClinPred		0.039	T
GERP RS		-8.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.048
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35877957; hg19: chr20-62309679;