14-100883594-C-T

Position:

• chr14-100883594-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134888.3(RTL1):​c.1195G>A​(p.Glu399Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,551,348 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (21 hom.)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.363

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)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038824975).
• BP6: Variant 14-100883594-C-T is Benign according to our data. Variant chr14-100883594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 718356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.1195G>A	p.Glu399Lys	missense_variant	4/4	ENST00000649591.1	NP_001128360.1
RTL1	XM_047431358.1	c.1195G>A	p.Glu399Lys	missense_variant	3/3		XP_047287314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.1195G>A	p.Glu399Lys	missense_variant	4/4		NM_001134888.3	ENSP00000497482	P1
MIR493HG	ENST00000699458.1	n.538C>T		non_coding_transcript_exon_variant	1/6

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00417 AC: 642 AN: 153828 Hom.: 4 AF XY: 0.00442 AC XY: 361 AN XY: 81652

Gnomad AFR exome AF: 0.000759

Gnomad AMR exome AF: 0.000891

Gnomad ASJ exome AF: 0.000825

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00512 AC: 7170 AN: 1399178 Hom.: 21 Cov.: 90 AF XY: 0.00501 AC XY: 3454 AN XY: 690096

Gnomad4 AFR exome AF: 0.000728

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.00544

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74386

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.00574

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00481 Hom.: 8

Bravo AF: 0.00295

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00754 AC: 24

ExAC AF: 0.00247 AC: 61

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MIR493HG: BS2; RTL1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.64	.;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.94	.;N
REVEL	Benign	0.16
Sift	Benign	0.32	.;T
Sift4G	Pathogenic	0.0	.;D
Vest4		0.12
MVP		0.14
MPC		0.75
ClinPred		0.0088	T
GERP RS		2.6
Varity_R		0.075
gMVP		0.37

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: rs142029300; hg19: chr14-101349931; COSMIC: COSV66016616; COSMIC: COSV66016616;