NM_001134888.3:c.3644G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1215C) has been classified as Uncertain significance.

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

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 783050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134888.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL1	NM_001134888.3	MANE Select	c.3644G>A	p.Arg1215His	missense	Exon 4 of 4	NP_001128360.1	A6NKG5
RTL1	NM_001425285.1		c.3644G>A	p.Arg1215His	missense	Exon 3 of 3	NP_001412214.1	A6NKG5
MIR431	NR_029965.1		n.*25C>T		downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL1	ENST00000649591.1	MANE Select	c.3644G>A	p.Arg1215His	missense	Exon 4 of 4	ENSP00000497482.1	A6NKG5
MIR493HG	ENST00000637474.1	TSL:5	n.109-8504C>T		intron	N/A
MIR431	ENST00000385266.1	TSL:6	n.*25C>T		downstream_gene	N/A

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

GnomAD2 exomes

AF:

0.00510

AC:

840

AN:

164694

AF XY:

0.00522

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 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

African (AFR)

AF:

0.00100

AC:

AN:

31950

American (AMR)

AF:

0.00246

AC:

AN:

37034

Ashkenazi Jewish (ASJ)

AF:

0.00405

AC:

100

AN:

24720

East Asian (EAS)

AF:

0.00160

AC:

AN:

36338

South Asian (SAS)

AF:

0.00324

AC:

254

AN:

78470

European-Finnish (FIN)

AF:

0.00780

AC:

380

AN:

48692

Middle Eastern (MID)

AF:

0.00458

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00801

AC:

8644

AN:

1079562

Other (OTH)

AF:

0.00717

AC:

417

AN:

58174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

680

1360

2041

2721

3401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00555

AC:

846

AN:

152302

Hom.:

Cov.:

AF XY:

0.00514

AC XY:

383

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41574

American (AMR)

AF:

0.00157

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5170

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00716

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00851

AC:

579

AN:

68012

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00641

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.57

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.11

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-1.3

PrimateAI

Benign

0.30

PROVEAN

Benign

0.23

REVEL

Benign

0.024

Sift

Benign

0.52

Sift4G

Benign

0.55

Vest4

0.023

MVP

0.081

MPC

0.74

ClinPred

0.0028

GERP RS

-1.5

Varity_R

0.018

gMVP

0.34

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over