Genetic Variant RTL1:p.Arg1279Leu (chr14-100880953-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001134888.3(RTL1):c.3836G>T(p.Arg1279Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

RTL1
NM_001134888.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.53

Variant links:

Genes affected

RTL1 (HGNC:14665): (retrotransposon Gag like 1) This gene is a retrotransposon-derived, paternally expressed imprinted gene that is highly expressed at the late fetal stage in both the fetus and placenta. It has an overlapping maternally expressed antisense transcript, which contains several microRNAs targeting the transcripts of this gene through an RNA interference (RNAi) mechanism. This gene is essential for maintenance of the fetal capillaries. [provided by RefSeq, Jul 2009]

RTL1 links:

MIR493HG (HGNC:55978): (MIR493 cluster host gene)

MIR493HG links:

MIR431 (HGNC:32027): (microRNA 431) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR431 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057420164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3 link	c.3836G>T	p.Arg1279Leu	missense_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1	A6NKG5B9EK54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTL1	ENST00000649591.1 link	c.3836G>T	p.Arg1279Leu	missense_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1	A6NKG5
MIR493HG	ENST00000637474.1 link	n.109-8696C>A		intron_variant	Intron 2 of 18	5
MIR431	ENST00000385266.1 link	n.-54C>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

AN:

1284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0172

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

AN:

43496

Hom.:

Cov.:

AF XY:

0.0000796

AC XY:

AN XY:

25114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00153

AC:

AN:

1306

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

AN XY:

814

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0161

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00108

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.8

DANN

Benign

0.94

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.21

.;N

REVEL

Benign

0.023

Sift

Benign

0.17

.;T

Sift4G

Benign

0.20

.;T

Vest4

0.084

MutPred

0.31

Gain of catalytic residue at P1277 (P = 0.001);Gain of catalytic residue at P1277 (P = 0.001);

MVP

0.088

MPC

0.74

ClinPred

0.068

GERP RS

-2.3

Varity_R

0.043

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over