Genetic Variant RRAGD:p.Gly34Ala (chr6-89411893-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_021244.5(RRAGD):c.101G>C(p.Gly34Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,394,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

RRAGD
NM_021244.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.589

Publications

2 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)
inherited renal tubular disease
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

RRAGD links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 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=0.19995049).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021244.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAGD	NM_021244.5	MANE Select	c.101G>C	p.Gly34Ala	missense	Exon 1 of 7	NP_067067.1	Q9NQL2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRAGD	ENST00000369415.9	TSL:1 MANE Select	c.101G>C	p.Gly34Ala	missense	Exon 1 of 7	ENSP00000358423.4	Q9NQL2-1
RRAGD	ENST00000886444.1		c.101G>C	p.Gly34Ala	missense	Exon 2 of 8	ENSP00000556503.1
RRAGD	ENST00000936138.1		c.101G>C	p.Gly34Ala	missense	Exon 2 of 8	ENSP00000606197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000679

AC:

AN:

147240

AF XY:

0.0000126

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.00000645

AC:

AN:

1394678

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

688884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31706

American (AMR)

AF:

0.00

AC:

AN:

36434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

36120

South Asian (SAS)

AF:

0.00

AC:

AN:

79762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000833

AC:

AN:

1080500

Other (OTH)

AF:

0.00

AC:

AN:

58026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.018

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.59

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.1

REVEL

Benign

0.10

Sift

Benign

0.057

Sift4G

Benign

0.090

Polyphen

0.44

Vest4

0.11

MutPred

0.21

Gain of catalytic residue at G34 (P = 0.1444)

MVP

0.30

MPC

1.7

ClinPred

0.78

GERP RS

3.7

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.18

gMVP

0.27

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over