6-89380270-A-G

Position:

• chr6-89380270-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021244.5(RRAGD):​c.542T>C​(p.Val181Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RRAGD NM_021244.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAGD	NM_021244.5	c.542T>C	p.Val181Ala	missense_variant	3/7	ENST00000369415.9	NP_067067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRAGD	ENST00000369415.9	c.542T>C	p.Val181Ala	missense_variant	3/7	1	NM_021244.5	ENSP00000358423.4
RRAGD	ENST00000359203.3	c.89T>C	p.Val30Ala	missense_variant	2/6	2		ENSP00000352131.2
RRAGD	ENST00000492783.1	n.566T>C		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.542T>C (p.V181A) alteration is located in exon 3 (coding exon 3) of the RRAGD gene. This alteration results from a T to C substitution at nucleotide position 542, causing the valine (V) at amino acid position 181 to be replaced by an alanine (A). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.064	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.092	T;D
Sift4G	Benign	0.081	T;T
Polyphen		0.57	P;.
Vest4		0.78
MutPred		0.74		Gain of catalytic residue at V181 (P = 0.062);.;
MVP		0.81
MPC		1.8
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.61
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1582508473; hg19: chr6-90089989;