6-89387467-G-A

Variant names:

• chr6-89387467-G-A
• NM_021244.5:c.272C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_021244.5(RRAGD):​c.272C>T​(p.Thr91Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRAGD NM_021244.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60

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, 0.796
• PP5: Variant 6-89387467-G-A is Pathogenic according to our data. Variant chr6-89387467-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3765497.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAGD	NM_021244.5	c.272C>T	p.Thr91Ile	missense_variant	Exon 2 of 7	ENST00000369415.9	NP_067067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAGD	ENST00000369415.9	c.272C>T	p.Thr91Ile	missense_variant	Exon 2 of 7	1	NM_021244.5	ENSP00000358423.4
RRAGD	ENST00000359203.3	c.-9-7100C>T		intron_variant	Intron 1 of 5	2		ENSP00000352131.2
RRAGD	ENST00000492783.1	n.296C>T		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypomagnesemia 7, renal, with or without dilated cardiomyopathy Pathogenic:1

-

Molecular Physiology Group, Radboudumc

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RRAGD NM_021244.5:c.272C>T variant is a heterozygous missense variant found in four individuals with kidney tubulopathy (internal data). These phenotypes fit other heterozygous missense variants in RRAGD previously reported (PMID 34607910, 37188688, and 38372174) in autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD, OMIM: 620152) indicating this variant is highly likely to be associated with this disease. The variant is not present in gnomAD. Inheritance pattern is still being investigated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.62		Loss of disorder (P = 0.0374);
MVP		0.62
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-90097186;