X-112454805-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001395362.2(RTL4):c.77G>A(p.Arg26Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000894 in 1,207,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 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. R26W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000090 ( 0 hom. 38 hem. )

Consequence

RTL4
NM_001395362.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.233

Variant links:

Genes affected

RTL4 (HGNC:25214): (retrotransposon Gag like 4) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Predicted to act upstream of or within cognition and norepinephrine metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

RTL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07135719).

BP6

Variant X-112454805-G-A is Benign according to our data. Variant chrX-112454805-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3156912.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTL4	NM_001395362.2 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	5/5	ENST00000695839.1
RTL4	NM_001004308.3 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
RTL4	ENST00000695839.1 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	5/5	NM_001395362.2	P1
RTL4	ENST00000340433.4 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	4/4		P1
RTL4	ENST00000695808.1 linkuse as main transcript	c.77G>A	p.Arg26Gln	missense_variant	3/3		P1

Frequencies

GnomAD3 genomes

AF:

0.0000810

AC:

AN:

111069

Hom.:

Cov.:

AF XY:

0.0000901

AC XY:

AN XY:

33307

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000170

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000335

AC:

AN:

179273

Hom.:

AF XY:

0.0000623

AC XY:

AN XY:

64173

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000903

AC:

AN:

1096365

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

361941

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000372

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000810

AC:

AN:

111069

Hom.:

Cov.:

AF XY:

0.0000901

AC XY:

AN XY:

33307

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000170

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-1.0

Cadd

Benign

0.044

Dann

Benign

0.23

DEOGEN2

Benign

0.0052

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.49

M_CAP

Benign

0.0029

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.18

PROVEAN

Benign

1.2

REVEL

Benign

0.020

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.026

MutPred

0.44

Loss of catalytic residue at R26 (P = 0.0416);

MVP

0.38

MPC

0.013

ClinPred

0.018

GERP RS

0.13

Varity_R

0.023

gMVP

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over