Variant X-72129943-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001024455.4(RTL5):c.1598G>A(p.Arg533His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

RTL5
NM_001024455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08734807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RTL5	NM_001405151.1 linkuse as main transcript	c.1598G>A	p.Arg533His	missense_variant	1/1	ENST00000609883.3
RTL5	NM_001024455.4 linkuse as main transcript	c.1598G>A	p.Arg533His	missense_variant	1/2
NHSL2	NM_001013627.3 linkuse as main transcript	c.281-2136C>T		intron_variant		ENST00000633930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTL5	ENST00000609883.3 linkuse as main transcript	c.1598G>A	p.Arg533His	missense_variant	1/1		NM_001405151.1	P1
NHSL2	ENST00000633930.2 linkuse as main transcript	c.281-2136C>T		intron_variant		5	NM_001013627.3	P3	Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33590

show subpopulations

Gnomad AFR

AF:

0.0000655

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097797

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363229

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000359

AC:

AN:

111386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33590

show subpopulations

Gnomad4 AFR

AF:

0.0000655

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:

0.0000378

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.1598G>A (p.R533H) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a G to A substitution at nucleotide position 1598, causing the arginine (R) at amino acid position 533 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0034

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.61

M_CAP

Benign

0.0048

MetaRNN

Benign

0.087

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.48

Sift4G

Pathogenic

0.0010

Polyphen

0.013

Vest4

0.16

MutPred

0.26

Loss of MoRF binding (P = 0.0428);

MVP

0.11

ClinPred

0.13

GERP RS

3.2

Varity_R

0.035

gMVP

0.083

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