rs76090066

Variant names:

• chr14-100881018-C-T
• rs76090066
• NM_001134888.3:c.3771G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001134888.3(RTL1):​c.3771G>A​(p.Gln1257Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,590,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: RTL1 NM_001134888.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.21
• Publications: 8 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]

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]

MIR493HG (HGNC:55978): (MIR493 cluster host gene)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 14-100881018-C-T is Benign according to our data. Variant chr14-100881018-C-T is described in ClinVar as Benign. ClinVar VariationId is 711467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.21 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL1	NM_001134888.3	c.3771G>A	p.Gln1257Gln	synonymous_variant	Exon 4 of 4	ENST00000649591.1	NP_001128360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL1	ENST00000649591.1	c.3771G>A	p.Gln1257Gln	synonymous_variant	Exon 4 of 4		NM_001134888.3	ENSP00000497482.1
MIR431	ENST00000385266.1	n.12C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MIR493HG	ENST00000637474.1	n.109-8631C>T		intron_variant	Intron 2 of 18	5

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 216 AN: 213250 AF XY: 0.000893

Gnomad AFR exome AF: 0.000540

Gnomad AMR exome AF: 0.000159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000426

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00170 AC: 2440 AN: 1437884 Hom.: 3 Cov.: 88 AF XY: 0.00168 AC XY: 1195 AN XY: 713116

African (AFR) AF: 0.000303 AC: 10 AN: 32952

American (AMR) AF: 0.000143 AC: 6 AN: 41960

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25720

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.000364 AC: 30 AN: 82486

European-Finnish (FIN) AF: 0.000571 AC: 29 AN: 50782

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.00208 AC: 2289 AN: 1100474

Other (OTH) AF: 0.00121 AC: 72 AN: 59476

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.00106 AC XY: 79 AN XY: 74476

African (AFR) AF: 0.000289 AC: 12 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		3.2
Mutation Taster		=100/0	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: rs76090066; hg19: chr14-101347355;