14-100881332-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001134888.3(RTL1):c.3457G>A(p.Val1153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,550,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

RTL1
NM_001134888.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.59

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005225569).

BP6

Variant 14-100881332-C-T is Benign according to our data. Variant chr14-100881332-C-T is described in ClinVar as [Benign]. Clinvar id is 739623.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3 link	c.3457G>A	p.Val1153Ile	missense_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1	A6NKG5B9EK54
RTL1	NM_001425285.1 link	c.3457G>A	p.Val1153Ile	missense_variant	Exon 3 of 3		NP_001412214.1
MIR431	NR_029965.1 link	n.*212C>T		downstream_gene_variant
MIR431	unassigned_transcript_2365	n.*242C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTL1	ENST00000649591.1 link	c.3457G>A	p.Val1153Ile	missense_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1	A6NKG5
MIR493HG	ENST00000637474.1 link	n.109-8317C>T		intron_variant	Intron 2 of 18	5
MIR431	ENST00000385266.1 link	n.*212C>T		downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000316

AC:

AN:

154972

AF XY:

0.000364

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00174

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000336

Gnomad OTH exome

AF:

0.000913

GnomAD4 exome

AF:

0.000129

AC:

180

AN:

1398282

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

118

AN XY:

689668

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

AC:

AN:

31598

Gnomad4 AMR exome

AF:

0.0000280

AC:

AN:

35700

Gnomad4 ASJ exome

AF:

0.0000397

AC:

AN:

25182

Gnomad4 EAS exome

AF:

0.000420

AC:

AN:

35738

Gnomad4 SAS exome

AF:

0.00114

AC:

AN:

79236

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

48176

Gnomad4 NFE exome

AF:

0.0000371

AC:

AN:

1078964

Gnomad4 Remaining exome

AF:

0.000500

AC:

AN:

57990

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<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:

0.000276

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000192

AC:

0.000192428

AN:

0.000192428

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000653595

AN:

0.0000653595

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00251

AC:

0.00251451

AN:

0.00251451

Gnomad4 SAS

AF:

0.00373

AC:

0.00372671

AN:

0.00372671

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294005

AN:

0.0000294005

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.0000678

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000542

AC:

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.043

DANN

Benign

0.94

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.37

.;T

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

0.44

.;N

REVEL

Benign

0.0040

Sift

Benign

1.0

.;T

Sift4G

Benign

0.35

.;T

Vest4

0.058

MutPred

0.39

Gain of catalytic residue at N1156 (P = 0.001);Gain of catalytic residue at N1156 (P = 0.001);

MVP

0.030

MPC

0.48

ClinPred

0.0041

GERP RS

-4.0

Varity_R

0.018

gMVP

0.15

Mutation Taster

=99/1

polymorphism

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