14-100881111-A-G

Position:

• chr14-100881111-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001134888.3(RTL1):​c.3678T>C​(p.Gly1226=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000531 in 1,581,560 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: RTL1 NM_001134888.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.45

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]

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 14-100881111-A-G is Benign according to our data. Variant chr14-100881111-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 795086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.45 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.3678T>C	p.Gly1226=	synonymous_variant	4/4	ENST00000649591.1	NP_001128360.1
MIR431	NR_029965.1	n.105A>G		non_coding_transcript_exon_variant	1/1
RTL1	XM_047431358.1	c.3678T>C	p.Gly1226=	synonymous_variant	3/3		XP_047287314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.3678T>C	p.Gly1226=	synonymous_variant	4/4		NM_001134888.3	ENSP00000497482	P1
MIR431	ENST00000385266.1	n.105A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152096 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000691 AC: 14 AN: 202614 Hom.: 1 AF XY: 0.0000551 AC XY: 6 AN XY: 108884

Gnomad AFR exome AF: 0.000975

Gnomad AMR exome AF: 0.0000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000394

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000385 AC: 55 AN: 1429346 Hom.: 0 Cov.: 88 AF XY: 0.0000325 AC XY: 23 AN XY: 707850

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.0000243

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.000186

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152214 Hom.: 1 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74432

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.93
DANN	Benign	0.75

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: rs138412993; hg19: chr14-101347448;