6-89411893-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_021244.5(RRAGD):c.101G>A(p.Gly34Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,546,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.2e-7 ( 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.19967231).

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>A	p.Gly34Glu	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>A	p.Gly34Glu	missense	Exon 1 of 7	ENSP00000358423.4	Q9NQL2-1
RRAGD	ENST00000886444.1		c.101G>A	p.Gly34Glu	missense	Exon 2 of 8	ENSP00000556503.1
RRAGD	ENST00000936138.1		c.101G>A	p.Gly34Glu	missense	Exon 2 of 8	ENSP00000606197.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688884

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31706

American (AMR)

AF:

0.0000274

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:

0.00

AC:

AN:

1080500

Other (OTH)

AF:

0.00

AC:

AN:

58026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

AF:

0.00000658

AC:

AN:

151950

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74200

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0061

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.59

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.97

REVEL

Benign

0.24

Sift

Benign

0.037

Sift4G

Uncertain

0.017

Polyphen

0.28

Vest4

0.14

MutPred

0.20

Gain of loop (P = 0.069)

MVP

0.17

MPC

2.0

ClinPred

0.83

GERP RS

3.7

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.21

gMVP

0.19

Mutation Taster

=87/13

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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