Variant X-72130403-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001024455.4(RTL5):c.1138G>A(p.Glu380Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,173,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 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 0.00076 ( 0 hom., 19 hem., cov: 22)

Exomes 𝑓: 0.000090 ( 0 hom. 25 hem. )

Consequence

RTL5
NM_001024455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.101

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049708486).

BS2

High Hemizygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.281-1676C>T		intron_variant		ENST00000633930.2	NP_001013649.2	Q5HYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3 link	c.1138G>A	p.Glu380Lys	missense_variant	1/1	6		ENSP00000476792.1		Q5HYW3
NHSL2	ENST00000633930.2 link	c.281-1676C>T		intron_variant		5	NM_001013627.3	ENSP00000488668.1		Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.000773

AC:

AN:

109978

Hom.:

Cov.:

AF XY:

0.000621

AC XY:

AN XY:

32216

show subpopulations

Gnomad AFR

AF:

0.00252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000683

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:

0.00

Gnomad OTH

AF:

0.00136

GnomAD3 exomes

AF:

0.000115

AC:

AN:

147256

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

45270

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.000130

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:

0.00

Gnomad OTH exome

AF:

0.000257

GnomAD4 exome

AF:

0.0000903

AC:

AN:

1062985

Hom.:

Cov.:

AF XY:

0.0000740

AC XY:

AN XY:

338025

show subpopulations

Gnomad4 AFR exome

AF:

0.00312

Gnomad4 AMR exome

AF:

0.0000947

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000579

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000245

Gnomad4 OTH exome

AF:

0.000178

GnomAD4 genome

AF:

0.000763

AC:

AN:

110027

Hom.:

Cov.:

AF XY:

0.000589

AC XY:

AN XY:

32275

show subpopulations

Gnomad4 AFR

AF:

0.00249

Gnomad4 AMR

AF:

0.000682

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00135

Alfa

AF:

0.000490

Hom.:

Bravo

AF:

0.000994

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000176

AC:

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 23, 2024

The c.1138G>A (p.E380K) 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 1138, causing the glutamic acid (E) at amino acid position 380 to be replaced by a lysine (K). 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

0.084

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0014

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.50

M_CAP

Benign

0.024

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.31

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.11

MVP

0.048

ClinPred

0.031

GERP RS

1.4

Varity_R

0.059

gMVP

0.24

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