chr14-100880947-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001134888.3(RTL1):c.3842G>C(p.Arg1281Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1281H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RTL1
NM_001134888.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.675

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11434707).

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.3842G>C	p.Arg1281Pro	missense	Exon 4 of 4	NP_001128360.1	A6NKG5
RTL1	NM_001425285.1		c.3842G>C	p.Arg1281Pro	missense	Exon 3 of 3	NP_001412214.1	A6NKG5
MIR431	NR_029965.1		n.-60C>G		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL1	ENST00000649591.1	MANE Select	c.3842G>C	p.Arg1281Pro	missense	Exon 4 of 4	ENSP00000497482.1	A6NKG5
MIR493HG	ENST00000637474.1	TSL:5	n.109-8702C>G		intron	N/A
MIR431	ENST00000385266.1	TSL:6	n.-60C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000247

AC:

AN:

4050

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000395

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000271

AC:

AN:

81200

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

AN XY:

44384

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

1242

American (AMR)

AF:

0.000273

AC:

AN:

3658

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

3872

East Asian (EAS)

AF:

0.00467

AC:

AN:

428

South Asian (SAS)

AF:

0.000411

AC:

AN:

12154

European-Finnish (FIN)

AF:

0.0000637

AC:

AN:

15700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

806

European-Non Finnish (NFE)

AF:

0.000270

AC:

AN:

40746

Other (OTH)

AF:

0.000386

AC:

AN:

2594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.284

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000247

AC:

AN:

4050

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

2184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

650

American (AMR)

AF:

0.00

AC:

AN:

210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

100

East Asian (EAS)

AF:

0.00

AC:

AN:

238

South Asian (SAS)

AF:

0.00

AC:

AN:

126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000395

AC:

AN:

2532

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.42

M_CAP

Benign

0.052

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.68

PrimateAI

Benign

0.33

PROVEAN

Benign

0.18

REVEL

Benign

0.098

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Vest4

0.15

MutPred

0.29

Gain of catalytic residue at P1280 (P = 5e-04)

MVP

0.22

MPC

0.87

ClinPred

0.28

GERP RS

-0.65

Varity_R

0.13

gMVP

0.11

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over