9-19050011-C-T

Variant names:

• chr9-19050011-C-T
• rs924116761
• NM_006570.5:c.352C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006570.5(RRAGA):​c.352C>T​(p.Pro118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RRAGA NM_006570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75
• Publications: 0 publications found

Genes affected

RRAGA (HGNC:16963): (Ras related GTP binding A) Enables several functions, including GTP binding activity; protein dimerization activity; and ubiquitin protein ligase binding activity. Involved in several processes, including cellular response to amino acid starvation; negative regulation of autophagy; and positive regulation of TORC1 signaling. Located in lysosome and nucleus. Colocalizes with GATOR1 complex. [provided by Alliance of Genome Resources, Apr 2022]

RRAGA Gene-Disease associations (from GenCC):

• cataract

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40928236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006570.5. 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
	RRAGA	NM_006570.5	MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 1 of 1	NP_006561.1	Q7L523

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAGA	ENST00000380527.3	TSL:6 MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 1 of 1	ENSP00000369899.1	Q7L523

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.052
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.32
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		0.027	B
Vest4		0.38
MutPred		0.76		Loss of stability (P = 0.115)
MVP		0.75
MPC		1.5
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.49
gMVP		0.89
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs924116761; hg19: chr9-19050009;