14-100883216-A-G

Position:

• chr14-100883216-A-G

Variant summary

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

The NM_001134888.3(RTL1):​c.1573T>C​(p.Phe525Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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=0.30429342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.1573T>C	p.Phe525Leu	missense_variant	4/4	ENST00000649591.1	NP_001128360.1
RTL1	NM_001425285.1	c.1573T>C	p.Phe525Leu	missense_variant	3/3		NP_001412214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.1573T>C	p.Phe525Leu	missense_variant	4/4		NM_001134888.3	ENSP00000497482.1
MIR493HG	ENST00000699458.1	n.160A>G		non_coding_transcript_exon_variant	1/6
MIR493HG	ENST00000637474.1	n.109-6433A>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 89

GnomAD4 genome Cov.: 32

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

Oct 29, 2024

The c.1573T>C (p.F525L) 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 1573, causing the phenylalanine (F) at amino acid position 525 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.50	.;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	.;N
REVEL	Benign	0.17
Sift	Benign	0.29	.;T
Sift4G	Pathogenic	0.0	.;D
Vest4		0.49
MutPred		0.45		Gain of catalytic residue at R522 (P = 5e-04);Gain of catalytic residue at R522 (P = 5e-04);
MVP		0.31
MPC		1.5
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.82

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: chr14-101349553;