Genetic Variant RTL1:p.Gln1257Gln (chr14-100881018-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_001134888.3(RTL1):c.3771G>A(p.Gln1257Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,590,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 3 hom. )

Consequence

RTL1
NM_001134888.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.21

Publications

8 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:

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:

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

MIR493HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP6

Variant 14-100881018-C-T is Benign according to our data. Variant chr14-100881018-C-T is described in ClinVar as Benign. ClinVar VariationId is 711467.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=3.21 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 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
RTL1	NM_001134888.3	MANE Select	c.3771G>A	p.Gln1257Gln	synonymous	Exon 4 of 4	NP_001128360.1
RTL1	NM_001425285.1		c.3771G>A	p.Gln1257Gln	synonymous	Exon 3 of 3	NP_001412214.1
MIR431	NR_029965.1		n.12C>T		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RTL1	ENST00000649591.1	MANE Select	c.3771G>A	p.Gln1257Gln	synonymous	Exon 4 of 4	ENSP00000497482.1
MIR431	ENST00000385266.1	TSL:6	n.12C>T		non_coding_transcript_exon	Exon 1 of 1
MIR493HG	ENST00000637474.1	TSL:5	n.109-8631C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00101

AC:

216

AN:

213250

AF XY:

0.000893

show subpopulations

Gnomad AFR exome

AF:

0.000540

Gnomad AMR exome

AF:

0.000159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000426

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

AF:

0.00170

AC:

2440

AN:

1437884

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1195

AN XY:

713116

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

32952

American (AMR)

AF:

0.000143

AC:

AN:

41960

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25720

East Asian (EAS)

AF:

0.00

AC:

AN:

38334

South Asian (SAS)

AF:

0.000364

AC:

AN:

82486

European-Finnish (FIN)

AF:

0.000571

AC:

AN:

50782

Middle Eastern (MID)

AF:

0.000526

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00208

AC:

2289

AN:

1100474

Other (OTH)

AF:

0.00121

AC:

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

173

346

519

692

865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00111

AC:

169

AN:

152304

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41576

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00221

AC:

150

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00181

Hom.:

Bravo

AF:

0.00102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

3.2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over