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GeneBe

16-66925145-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004165.3(RRAD):c.35G>C(p.Gly12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,226,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RRAD
NM_004165.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2204994).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RRADNM_004165.3 linkuse as main transcriptc.35G>C p.Gly12Ala missense_variant 2/5 ENST00000299759.11
RRADNM_001128850.2 linkuse as main transcriptc.35G>C p.Gly12Ala missense_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RRADENST00000299759.11 linkuse as main transcriptc.35G>C p.Gly12Ala missense_variant 2/51 NM_004165.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000261
AC:
28
AN:
1074712
Hom.:
0
Cov.:
30
AF XY:
0.0000256
AC XY:
13
AN XY:
508074
show subpopulations
Gnomad4 AFR exome
AF:
0.0000883
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:
0.0000283
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74246
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000126
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2021The c.35G>C (p.G12A) alteration is located in exon 2 (coding exon 1) of the RRAD gene. This alteration results from a G to C substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 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
Benign
0.079
BayesDel_addAF
Benign
-0.059
T
BayesDel_noAF
Benign
-0.32
Cadd
Benign
20
Dann
Benign
0.50
DEOGEN2
Benign
0.15
T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.55
T;.
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.98
N;N
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
0.22
N;N
REVEL
Benign
0.21
Sift
Benign
1.0
T;T
Sift4G
Benign
0.70
T;T
Polyphen
1.0
D;D
Vest4
0.16
MutPred
0.17
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
0.72
MPC
1.5
ClinPred
0.40
T
GERP RS
3.4
Varity_R
0.082
gMVP
0.33

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs758327096; hg19: chr16-66959048; API