X-72130404-C-A

Variant summary

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

The NM_001024455.4(RTL5):​c.1137G>T​(p.Glu379Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,187,923 control chromosomes in the GnomAD database, including 1 homozygotes. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 21)
Exomes 𝑓: 0.000070 ( 1 hom. 45 hem. )

Consequence

RTL5
NM_001024455.4 missense

Scores

2
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.496
Variant links:
Genes affected
RTL5 (HGNC:29430): (retrotransposon Gag like 5)
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]

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=0.0062578917).
BS2
High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHSL2NM_001013627.3 linkc.281-1675C>A intron_variant Intron 1 of 7 ENST00000633930.2 NP_001013649.2 Q5HYW2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RTL5ENST00000609883.3 linkc.1137G>T p.Glu379Asp missense_variant Exon 1 of 1 6 ENSP00000476792.1 Q5HYW3
NHSL2ENST00000633930.2 linkc.281-1675C>A intron_variant Intron 1 of 7 5 NM_001013627.3 ENSP00000488668.1 Q5HYW2-1

Frequencies

GnomAD3 genomes
AF:
0.0000273
AC:
3
AN:
109928
Hom.:
0
Cov.:
21
AF XY:
0.0000621
AC XY:
2
AN XY:
32194
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:
0.000801
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000190
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
16
AN:
148102
Hom.:
0
AF XY:
0.000284
AC XY:
13
AN XY:
45764
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:
0.000990
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000696
AC:
75
AN:
1077995
Hom.:
1
Cov.:
32
AF XY:
0.000129
AC XY:
45
AN XY:
348935
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:
0.00126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000482
Gnomad4 OTH exome
AF:
0.000110
GnomAD4 genome
AF:
0.0000273
AC:
3
AN:
109928
Hom.:
0
Cov.:
21
AF XY:
0.0000621
AC XY:
2
AN XY:
32194
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:
0.000801
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000190
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.000227
AC:
27

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1137G>T (p.E379D) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a G to T substitution at nucleotide position 1137, causing the glutamic acid (E) at amino acid position 379 to be replaced by an aspartic acid (D). 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
0.13
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
12
DANN
Uncertain
0.97
DEOGEN2
Benign
0.0015
T
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.0063
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.33
T
Sift4G
Uncertain
0.058
T
Polyphen
0.0020
B
Vest4
0.027
MutPred
0.22
Gain of MoRF binding (P = 0.1105);
MVP
0.030
ClinPred
0.030
T
GERP RS
1.1
Varity_R
0.15
gMVP
0.16

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.

Other links and lift over

dbSNP: rs763629425; hg19: chrX-71350254; API