14-100880774-G-T

Position:

• chr14-100880774-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134888.3(RTL1):​c.4015C>A​(p.Pro1339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0530

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069279075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.4015C>A	p.Pro1339Thr	missense_variant	4/4	ENST00000649591.1	NP_001128360.1
RTL1	XM_047431358.1	c.4015C>A	p.Pro1339Thr	missense_variant	3/3		XP_047287314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.4015C>A	p.Pro1339Thr	missense_variant	4/4		NM_001134888.3	ENSP00000497482	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.4015C>A (p.P1339T) alteration is located in exon 1 (coding exon 1) of the RTL1 gene. This alteration results from a C to A substitution at nucleotide position 4015, causing the proline (P) at amino acid position 1339 to be replaced by a threonine (T). 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	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.51	.;N
REVEL	Benign	0.0060
Sift	Uncertain	0.015	.;D
Sift4G	Benign	0.073	.;T
Vest4		0.090
MutPred		0.21		Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);
MVP		0.13
MPC		0.78
ClinPred		0.093	T
GERP RS		0.82
Varity_R		0.065
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-101347111;