NM_001134888.3:c.3644G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001134888.3(RTL1):c.3644G>A(p.Arg1215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,552,920 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 47 hom. )

Consequence

RTL1
NM_001134888.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047321916).

BP6

Variant 14-100881145-C-T is Benign according to our data. Variant chr14-100881145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 783050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-100881145-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3 link	c.3644G>A	p.Arg1215His	missense_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1	A6NKG5B9EK54
RTL1	NM_001425285.1 link	c.3644G>A	p.Arg1215His	missense_variant	Exon 3 of 3		NP_001412214.1
MIR431	NR_029965.1 link	n.*25C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTL1	ENST00000649591.1 link	c.3644G>A	p.Arg1215His	missense_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1	A6NKG5
MIR493HG	ENST00000637474.1 link	n.109-8504C>T		intron_variant	Intron 2 of 18	5
MIR431	ENST00000385266.1 link	n.*25C>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00555

AC:

845

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00716

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00850

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00510

AC:

840

AN:

164694

Hom.:

AF XY:

0.00522

AC XY:

454

AN XY:

86932

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.00173

Gnomad SAS exome

AF:

0.00302

Gnomad FIN exome

AF:

0.00661

Gnomad NFE exome

AF:

0.00771

Gnomad OTH exome

AF:

0.00432

GnomAD4 exome

AF:

0.00714

AC:

10002

AN:

1400618

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

4792

AN XY:

690640

show subpopulations

Gnomad4 AFR exome

AF:

0.00100

Gnomad4 AMR exome

AF:

0.00246

Gnomad4 ASJ exome

AF:

0.00405

Gnomad4 EAS exome

AF:

0.00160

Gnomad4 SAS exome

AF:

0.00324

Gnomad4 FIN exome

AF:

0.00780

Gnomad4 NFE exome

AF:

0.00801

Gnomad4 OTH exome

AF:

0.00717

GnomAD4 genome

AF:

0.00555

AC:

846

AN:

152302

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

383

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00716

Gnomad4 NFE

AF:

0.00851

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00700

Hom.:

Bravo

AF:

0.00513

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000641

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00376

AC:

433

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTL1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.57

DANN

Benign

0.93

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.30

PROVEAN

Benign

0.23

.;N

REVEL

Benign

0.024

Sift

Benign

0.52

.;T

Sift4G

Benign

0.55

.;T

Vest4

0.023

MVP

0.081

MPC

0.74

ClinPred

0.0028

GERP RS

-1.5

Varity_R

0.018

gMVP

0.34

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over