Genetic Variant RRAGC:p.Lys163Arg (chr1-38855861-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022157.4(RRAGC):c.488A>G(p.Lys163Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RRAGC
NM_022157.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

Variant links:

Genes affected

RRAGC (HGNC:19902): (Ras related GTP binding C) This gene encodes a member of the GTR/RAG GTP-binding protein family. The encoded protein is a monomeric guanine nucleotide-binding protein which forms a heterodimer with RRAGA and RRAGB and is primarily localized to the cytoplasm. The encoded protein promotes intracellular localization of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

RRAGC links:

ENSG00000273637 (HGNC:):

ENSG00000273637 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAGC	NM_022157.4 link	c.488A>G	p.Lys163Arg	missense_variant	Exon 3 of 7	ENST00000373001.4	NP_071440.1	Q9HB90
RRAGC	NM_001271851.2 link	c.386A>G	p.Lys129Arg	missense_variant	Exon 3 of 7		NP_001258780.1	Q9HB90B4DQ03B4DQG4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RRAGC	ENST00000373001.4 link	c.488A>G	p.Lys163Arg	missense_variant	Exon 3 of 7	1	NM_022157.4	ENSP00000362092.3	Q9HB90
RRAGC	ENST00000493015.1 link	n.185A>G		non_coding_transcript_exon_variant	Exon 2 of 5	3
ENSG00000273637	ENST00000622355.1 link	n.1239A>G		non_coding_transcript_exon_variant	Exon 8 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

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:

0.000192

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251372

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488A>G (p.K163R) alteration is located in exon 3 (coding exon 3) of the RRAGC gene. This alteration results from a A to G substitution at nucleotide position 488, causing the lysine (K) at amino acid position 163 to be replaced by an arginine (R). 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

0.077

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.25

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.54

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.64

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.34

REVEL

Benign

0.25

Sift

Benign

0.78

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.19

MutPred

0.33

Loss of ubiquitination at K163 (P = 0.0341);

MVP

0.59

MPC

0.62

ClinPred

0.10

GERP RS

4.9

Varity_R

0.26

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -1

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