Variant X-72129887-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001024455.4(RTL5):c.1654C>T(p.Arg552Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000804 in 1,207,043 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000086 ( 0 hom. 34 hem. )

Consequence

RTL5
NM_001024455.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.631

Variant links:

Genes affected

RTL5 (HGNC:29430): (retrotransposon Gag like 5)

RTL5 links:

NHSL2 (HGNC:33737): (NHS like 2) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NHSL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.092077255).

BP6

Variant X-72129887-G-A is Benign according to our data. Variant chrX-72129887-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2660896.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 34 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RTL5	NM_001405151.1 linkuse as main transcript	c.1654C>T	p.Arg552Cys	missense_variant	1/1	ENST00000609883.3	NP_001392080.1
RTL5	NM_001024455.4 linkuse as main transcript	c.1654C>T	p.Arg552Cys	missense_variant	1/2		NP_001019626.1
NHSL2	NM_001013627.3 linkuse as main transcript	c.281-2192G>A		intron_variant		ENST00000633930.2	NP_001013649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3 linkuse as main transcript	c.1654C>T	p.Arg552Cys	missense_variant	1/1		NM_001405151.1	ENSP00000476792	P1
NHSL2	ENST00000633930.2 linkuse as main transcript	c.281-2192G>A		intron_variant		5	NM_001013627.3	ENSP00000488668	P3	Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111845

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34009

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000569

AC:

AN:

175797

Hom.:

AF XY:

0.0000643

AC XY:

AN XY:

62231

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000765

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000858

AC:

AN:

1095198

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

361016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000940

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111845

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34009

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.0000377

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The c.1654C>T (p.R552C) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a C to T substitution at nucleotide position 1654, causing the arginine (R) at amino acid position 552 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

NHSL2: BS2; RTL5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0033

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.67

M_CAP

Benign

0.0076

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.69

Sift4G

Benign

0.20

Polyphen

0.10

Vest4

0.19

MutPred

0.40

Gain of catalytic residue at L553 (P = 0.0092);

MVP

0.20

ClinPred

0.048

GERP RS

1.8

Varity_R

0.071

gMVP

0.093

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