14-100880914-A-G

Variant names:

• chr14-100880914-A-G
• rs1474713451
• NM_001134888.3:c.3875T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134888.3(RTL1):​c.3875T>C​(p.Leu1292Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,156,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29785123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.3875T>C	p.Leu1292Pro	missense_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1
RTL1	NM_001425285.1	c.3875T>C	p.Leu1292Pro	missense_variant	Exon 3 of 3		NP_001412214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.3875T>C	p.Leu1292Pro	missense_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1
MIR493HG	ENST00000637474.1	n.109-8735A>G		intron_variant	Intron 2 of 18	5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.0000104 AC: 12 AN: 1156330 Hom.: 0 Cov.: 58 AF XY: 0.00000705 AC XY: 4 AN XY: 567030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000239

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3875T>C (p.L1292P) alteration is located in exon 1 (coding exon 1) of the RTL1 gene. This alteration results from a T to C substitution at nucleotide position 3875, causing the leucine (L) at amino acid position 1292 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Vest4		0.84
MutPred		0.58		Loss of helix (P = 3e-04);Loss of helix (P = 3e-04);
MVP		0.45
MPC		2.0
ClinPred		0.73	D
GERP RS		3.6
Varity_R		0.49
gMVP		0.50

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: rs1474713451; hg19: chr14-101347251;