16-66924855-G-C

Variant names:

• chr16-66924855-G-C
• rs751752299
• NM_004165.3:c.325C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004165.3(RRAD):​c.325C>G​(p.Arg109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000418 in 1,435,390 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: 0.0000042 (0 hom.)
• Consequence: RRAD NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

RRAD (HGNC:10446): (RRAD, Ras related glycolysis inhibitor and calcium channel regulator) Predicted to enable GTP binding activity and calcium channel regulator activity. Predicted to be involved in small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in plasma membrane. Implicated in type 2 diabetes mellitus. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31252345).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAD	NM_004165.3	c.325C>G	p.Arg109Gly	missense_variant	Exon 2 of 5	ENST00000299759.11	NP_004156.1
RRAD	NM_001128850.2	c.325C>G	p.Arg109Gly	missense_variant	Exon 2 of 5		NP_001122322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAD	ENST00000299759.11	c.325C>G	p.Arg109Gly	missense_variant	Exon 2 of 5	1	NM_004165.3	ENSP00000299759.6
RRAD	ENST00000566577.1	c.97C>G	p.Arg33Gly	missense_variant	Exon 1 of 4	5		ENSP00000462559.1
RRAD	ENST00000568915.5	c.118C>G	p.Arg40Gly	missense_variant	Exon 1 of 3	5		ENSP00000461995.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000174 AC: 4 AN: 229518 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000234

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: 0.00000418 AC: 6 AN: 1435390 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000153

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 Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325C>G (p.R109G) alteration is located in exon 2 (coding exon 1) of the RRAD gene. This alteration results from a C to G substitution at nucleotide position 325, causing the arginine (R) at amino acid position 109 to be replaced by a glycine (G). 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	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.069
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.22	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.010	N;N
REVEL	Uncertain	0.52
Sift	Benign	0.61	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.65	P;P
Vest4		0.51
MutPred		0.51		Loss of stability (P = 0.0098);Loss of stability (P = 0.0098);
MVP		0.85
MPC		1.4
ClinPred		0.35	T
GERP RS		4.1
Varity_R		0.51
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751752299; hg19: chr16-66958758;