Genetic Variant RTL1:p.Phe703Phe (chr14-100882680-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001134888.3(RTL1):c.2109T>C(p.Phe703Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 1,551,690 control chromosomes in the GnomAD database, including 429,054 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 43792 hom., cov: 31)

Exomes 𝑓: 0.74 ( 385262 hom. )

Consequence

RTL1
NM_001134888.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.48

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP7

Synonymous conserved (PhyloP=-2.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3 link	c.2109T>C	p.Phe703Phe	synonymous_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1	A6NKG5B9EK54
RTL1	NM_001425285.1 link	c.2109T>C	p.Phe703Phe	synonymous_variant	Exon 3 of 3		NP_001412214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1 link	c.2109T>C	p.Phe703Phe	synonymous_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1		A6NKG5
MIR493HG	ENST00000637474.1 link	n.109-6969A>G		intron_variant	Intron 2 of 18	5

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

114051

AN:

151910

Hom.:

43757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.835

Gnomad AMI

AF:

0.728

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.795

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.504

Gnomad FIN

AF:

0.805

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.767

Gnomad OTH

AF:

0.738

GnomAD2 exomes

AF:

0.665

AC:

105114

AN:

158068

AF XY:

0.662

show subpopulations

Gnomad AFR exome

AF:

0.838

Gnomad AMR exome

AF:

0.464

Gnomad ASJ exome

AF:

0.794

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.801

Gnomad NFE exome

AF:

0.764

Gnomad OTH exome

AF:

0.703

GnomAD4 exome

AF:

0.736

AC:

1029941

AN:

1399662

Hom.:

385262

Cov.:

AF XY:

0.729

AC XY:

503462

AN XY:

690324

show subpopulations

African (AFR)

AF:

0.839

AC:

26513

AN:

31600

American (AMR)

AF:

0.482

AC:

17218

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.794

AC:

19993

AN:

25180

East Asian (EAS)

AF:

0.452

AC:

16149

AN:

35736

South Asian (SAS)

AF:

0.504

AC:

39964

AN:

79236

European-Finnish (FIN)

AF:

0.804

AC:

39712

AN:

49396

Middle Eastern (MID)

AF:

0.659

AC:

3757

AN:

5700

European-Non Finnish (NFE)

AF:

0.764

AC:

824621

AN:

1079042

Other (OTH)

AF:

0.724

AC:

42014

AN:

58070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

18042

36083

54125

72166

90208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19946

39892

59838

79784

99730

<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:

0.751

AC:

114132

AN:

152028

Hom.:

43792

Cov.:

AF XY:

0.743

AC XY:

55193

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.835

AC:

34644

AN:

41472

American (AMR)

AF:

0.581

AC:

8880

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.795

AC:

2760

AN:

3470

East Asian (EAS)

AF:

0.460

AC:

2375

AN:

5162

South Asian (SAS)

AF:

0.505

AC:

2428

AN:

4808

European-Finnish (FIN)

AF:

0.805

AC:

8510

AN:

10568

Middle Eastern (MID)

AF:

0.755

AC:

222

AN:

294

European-Non Finnish (NFE)

AF:

0.767

AC:

52110

AN:

67964

Other (OTH)

AF:

0.731

AC:

1539

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1397

2795

4192

5590

6987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.751

Hom.:

77974

Bravo

AF:

0.738

Asia WGS

AF:

0.504

AC:

1753

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.19

(source)

DANN

Benign

0.35

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over