rs561504020

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_021244.5(RRAGD):​c.1137G>C​(p.Lys379Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RRAGD
NM_021244.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.190

Publications

0 publications found
Variant links:
Genes affected
RRAGD (HGNC:19903): (Ras related GTP binding D) RRAGD is a monomeric guanine nucleotide-binding protein, or G protein. By binding GTP or GDP, small G proteins act as molecular switches in numerous cell processes and signaling pathways.[supplied by OMIM, Apr 2004]
RRAGD Gene-Disease associations (from GenCC):
  • hypomagnesemia 7, renal, with or without dilated cardiomyopathy
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1976 (below the threshold of 3.09). Trascript score misZ: 2.3889 (below the threshold of 3.09). GenCC associations: The gene is linked to hypomagnesemia 7, renal, with or without dilated cardiomyopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.014571995).
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RRAGDNM_021244.5 linkc.1137G>C p.Lys379Asn missense_variant Exon 7 of 7 ENST00000369415.9 NP_067067.1 Q9NQL2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RRAGDENST00000369415.9 linkc.1137G>C p.Lys379Asn missense_variant Exon 7 of 7 1 NM_021244.5 ENSP00000358423.4 Q9NQL2-1
RRAGDENST00000359203.3 linkc.684G>C p.Lys228Asn missense_variant Exon 6 of 6 2 ENSP00000352131.2 Q9NQL2-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152140
Hom.:
0
Cov.:
32
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:
0.00212
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000517
AC:
13
AN:
251228
AF XY:
0.0000589
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000652
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461752
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727194
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.000554
AC:
22
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111928
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.447
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74432
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41556
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00212
AC:
11
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 29, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1137G>C (p.K379N) alteration is located in exon 7 (coding exon 7) of the RRAGD gene. This alteration results from a G to C substitution at nucleotide position 1137, causing the lysine (K) at amino acid position 379 to be replaced by an asparagine (N). 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
0.26
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
16
DANN
Benign
0.94
DEOGEN2
Benign
0.21
T;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.70
T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.015
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;.
PhyloP100
0.19
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.070
N;N
REVEL
Benign
0.11
Sift
Benign
0.43
T;T
Sift4G
Benign
0.32
T;T
Polyphen
0.0010
B;.
Vest4
0.18
MutPred
0.32
Loss of methylation at K379 (P = 0.0213);.;
MVP
0.25
MPC
0.90
ClinPred
0.029
T
GERP RS
1.4
Varity_R
0.084
gMVP
0.53
Mutation Taster
=65/35
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs561504020; hg19: chr6-90077841; API