14-100883117-G-T

Position:

• chr14-100883117-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001134888.3(RTL1):​c.1672C>A​(p.Pro558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,612,710 control chromosomes in the GnomAD database, including 447 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 32)
  • Exomes 𝑓: 0.022 (418 hom.)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.47

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]

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

MIR127 (HGNC:31509): (microRNA 127) 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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005568266).
• BP6: Variant 14-100883117-G-T is Benign according to our data. Variant chr14-100883117-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206198.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-100883117-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2502/152294) while in subpopulation NFE AF= 0.0255 (1733/68022). AF 95% confidence interval is 0.0245. There are 29 homozygotes in gnomad4. There are 1197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.1672C>A	p.Pro558Thr	missense_variant	4/4	ENST00000649591.1	NP_001128360.1
RTL1	XM_047431358.1	c.1672C>A	p.Pro558Thr	missense_variant	3/3		XP_047287314.1
MIR127	NR_029696.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.1672C>A	p.Pro558Thr	missense_variant	4/4		NM_001134888.3	ENSP00000497482	P1
MIR493HG	ENST00000699458.1	n.61G>T		non_coding_transcript_exon_variant	1/6
MIR127	ENST00000384876.3			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2503 AN: 152176 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0154 AC: 3824 AN: 247910 Hom.: 49 AF XY: 0.0159 AC XY: 2131 AN XY: 134230

Gnomad AFR exome AF: 0.00361

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00645

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0220 AC: 32199 AN: 1460416 Hom.: 418 Cov.: 89 AF XY: 0.0217 AC XY: 15754 AN XY: 726314

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.00781

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.0254

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0164 AC: 2502 AN: 152294 Hom.: 29 Cov.: 32 AF XY: 0.0161 AC XY: 1197 AN XY: 74460

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0214 Hom.: 81

Bravo AF: 0.0154

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00478 AC: 15

ESP6500EA AF: 0.0246 AC: 176

ExAC AF: 0.0149 AC: 1798

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0199

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.48	.;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.058
Sift	Benign	0.73	.;T
Sift4G	Benign	1.0	.;T
Vest4		0.011
MPC		0.67
ClinPred		0.0019	T
GERP RS		2.8
Varity_R		0.045
gMVP		0.46

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

Other links and lift over

dbSNP: rs41286560; hg19: chr14-101349454;