NM_001283009.2:c.3371A>C

Variant names:

• chr20-63695093-A-C
• rs786205702
• NM_001283009.2:c.3371A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001283009.2(RTEL1):​c.3371A>C​(p.His1124Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1124Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Pathogenic/Likely risk allele no assertion criteria provided P:2
• Conservation: PhyloP100: 4.71
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 20-63695093-A-C is Pathogenic according to our data. Variant chr20-63695093-A-C is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 190475.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.3371A>C	p.His1124Pro	missense	Exon 33 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.3443A>C	p.His1148Pro	missense	Exon 33 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.3371A>C	p.His1124Pro	missense	Exon 33 of 35	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.3371A>C	p.His1124Pro	missense	Exon 33 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.3443A>C	p.His1148Pro	missense	Exon 33 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.3371A>C	p.His1124Pro	missense	Exon 33 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely risk allele

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.37		Gain of glycosylation at H1124 (P = 0.0334)
MVP		0.94
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs786205702; hg19: chr20-62326446;