NM_001134888.3:c.3836G>T

Variant names:

• chr14-100880953-C-A
• rs769647776
• NM_001134888.3:c.3836G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001134888.3(RTL1):​c.3836G>T​(p.Arg1279Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1279H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.53
• Publications: 1 publications found

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)

MIR431 (HGNC:32027): (microRNA 431) 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057420164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134888.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL1	NM_001134888.3	MANE Select	c.3836G>T	p.Arg1279Leu	missense	Exon 4 of 4	NP_001128360.1	A6NKG5
	RTL1	NM_001425285.1		c.3836G>T	p.Arg1279Leu	missense	Exon 3 of 3	NP_001412214.1	A6NKG5
	MIR431	NR_029965.1		n.-54C>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL1	ENST00000649591.1	MANE Select	c.3836G>T	p.Arg1279Leu	missense	Exon 4 of 4	ENSP00000497482.1	A6NKG5
	MIR493HG	ENST00000637474.1	TSL:5	n.109-8696C>A		intron	N/A
	MIR431	ENST00000385266.1	TSL:6	n.-54C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 2 AN: 1284 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 7 AN: 43496 Hom.: 0 Cov.: 0 AF XY: 0.0000796 AC XY: 2 AN XY: 25114

African (AFR) AF: 0.00 AC: 0 AN: 414

American (AMR) AF: 0.00 AC: 0 AN: 1396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2580

East Asian (EAS) AF: 0.00 AC: 0 AN: 372

South Asian (SAS) AF: 0.00 AC: 0 AN: 8358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000357 AC: 7 AN: 19634

Other (OTH) AF: 0.00 AC: 0 AN: 1376

GnomAD4 genome AF: 0.00153 AC: 2 AN: 1306 Hom.: 0 Cov.: 0 AF XY: 0.00246 AC XY: 2 AN XY: 814

African (AFR) AF: 0.00 AC: 0 AN: 132

American (AMR) AF: 0.00 AC: 0 AN: 58

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 48

East Asian (EAS) AF: 0.0161 AC: 1 AN: 62

South Asian (SAS) AF: 0.00 AC: 0 AN: 22

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00108 AC: 1 AN: 926

Other (OTH) AF: 0.00 AC: 0 AN: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.8
DANN	Benign	0.94
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
PhyloP100		-3.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.023
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Vest4		0.084
MutPred		0.31		Gain of catalytic residue at P1277 (P = 0.001)
MVP		0.088
MPC		0.74
ClinPred		0.068	T
GERP RS		-2.3
Varity_R		0.043
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs769647776; hg19: chr14-101347290;