rs149145821

Variant names:

• chr20-63695185-G-A
• rs149145821
• NM_001283009.2:c.3463G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63695185-G-A
• chr20-63695185-G-T
• chr20-63695185-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001283009.2(RTEL1):​c.3463G>A​(p.Val1155Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000918 in 1,612,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1155L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -2.54
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041915655).

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.3463G>A	p.Val1155Met	missense	Exon 33 of 35	NP_001269938.1	Q9NZ71-6
	RTEL1	NM_032957.5		c.3535G>A	p.Val1179Met	missense	Exon 33 of 35	NP_116575.3	Q9NZ71-7
	RTEL1	NM_016434.4		c.3463G>A	p.Val1155Met	missense	Exon 33 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.3463G>A	p.Val1155Met	missense	Exon 33 of 35	ENSP00000353332.5	Q9NZ71-6
	RTEL1	ENST00000508582.7	TSL:2	c.3535G>A	p.Val1179Met	missense	Exon 33 of 35	ENSP00000424307.2	Q9NZ71-7
	RTEL1	ENST00000370018.7	TSL:1	c.3463G>A	p.Val1155Met	missense	Exon 33 of 35	ENSP00000359035.3	Q9NZ71-1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152038 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 34 AN: 245236 AF XY: 0.000150

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000829 AC: 121 AN: 1459940 Hom.: 0 Cov.: 35 AF XY: 0.0000936 AC XY: 68 AN XY: 726280

African (AFR) AF: 0.000687 AC: 23 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51770

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111818

Other (OTH) AF: 0.000149 AC: 9 AN: 60348

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74376

African (AFR) AF: 0.000434 AC: 18 AN: 41510

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.000158 AC: 19

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.1
DANN	Benign	0.74
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.3	L
PhyloP100		-2.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.11	B
Vest4		0.16
MVP		0.51
ClinPred		0.013	T
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.26
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149145821; hg19: chr20-62326538; COSMIC: COSV107250706; COSMIC: COSV107250706;