14-100881145-C-T

Variant names:

• chr14-100881145-C-T
• rs61993318
• NM_001134888.3:c.3644G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134888.3(RTL1):​c.3644G>A​(p.Arg1215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,552,920 control chromosomes in the GnomAD database, including 53 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1215C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (47 hom.)
• Consequence: RTL1 NM_001134888.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.26
• Publications: 11 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047321916).
• BP6: Variant 14-100881145-C-T is Benign according to our data. Variant chr14-100881145-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 783050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.3644G>A	p.Arg1215His	missense	Exon 4 of 4	NP_001128360.1	A6NKG5
	RTL1	NM_001425285.1		c.3644G>A	p.Arg1215His	missense	Exon 3 of 3	NP_001412214.1	A6NKG5
	MIR431	NR_029965.1		n.*25C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL1	ENST00000649591.1	MANE Select	c.3644G>A	p.Arg1215His	missense	Exon 4 of 4	ENSP00000497482.1	A6NKG5
	MIR493HG	ENST00000637474.1	TSL:5	n.109-8504C>T		intron	N/A
	MIR431	ENST00000385266.1	TSL:6	n.*25C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152184 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00716

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00850

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00510 AC: 840 AN: 164694 AF XY: 0.00522

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.00771

Gnomad OTH exome AF: 0.00432

GnomAD4 exome AF: 0.00714 AC: 10002 AN: 1400618 Hom.: 47 Cov.: 88 AF XY: 0.00694 AC XY: 4792 AN XY: 690640

African (AFR) AF: 0.00100 AC: 32 AN: 31950

American (AMR) AF: 0.00246 AC: 91 AN: 37034

Ashkenazi Jewish (ASJ) AF: 0.00405 AC: 100 AN: 24720

East Asian (EAS) AF: 0.00160 AC: 58 AN: 36338

South Asian (SAS) AF: 0.00324 AC: 254 AN: 78470

European-Finnish (FIN) AF: 0.00780 AC: 380 AN: 48692

Middle Eastern (MID) AF: 0.00458 AC: 26 AN: 5678

European-Non Finnish (NFE) AF: 0.00801 AC: 8644 AN: 1079562

Other (OTH) AF: 0.00717 AC: 417 AN: 58174

GnomAD4 genome AF: 0.00555 AC: 846 AN: 152302 Hom.: 6 Cov.: 33 AF XY: 0.00514 AC XY: 383 AN XY: 74470

African (AFR) AF: 0.00123 AC: 51 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5170

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00716 AC: 76 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00851 AC: 579 AN: 68012

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00641 Hom.: 8

Bravo AF: 0.00513

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000641 AC: 2

ESP6500EA AF: 0.00687 AC: 49

ExAC AF: 0.00376 AC: 433

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.57
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.024
Sift	Benign	0.52	T
Sift4G	Benign	0.55	T
Vest4		0.023
MVP		0.081
MPC		0.74
ClinPred		0.0028	T
GERP RS		-1.5
Varity_R		0.018
gMVP		0.34
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: rs61993318; hg19: chr14-101347482; COSMIC: COSV66016797; COSMIC: COSV66016797;