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GeneBe

16-66924885-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004165.3(RRAD):c.295G>T(p.Ala99Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,585,972 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: 𝑓 0.00042 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RRAD
NM_004165.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06434655).
BS2
High AC in GnomAd at 64 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RRADNM_004165.3 linkuse as main transcriptc.295G>T p.Ala99Ser missense_variant 2/5 ENST00000299759.11
RRADNM_001128850.2 linkuse as main transcriptc.295G>T p.Ala99Ser missense_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RRADENST00000299759.11 linkuse as main transcriptc.295G>T p.Ala99Ser missense_variant 2/51 NM_004165.3 P1
RRADENST00000566577.1 linkuse as main transcriptc.70G>T p.Ala24Ser missense_variant 1/45
RRADENST00000568915.5 linkuse as main transcriptc.91G>T p.Ala31Ser missense_variant 1/35

Frequencies

GnomAD3 genomes
AF:
0.000421
AC:
64
AN:
151992
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000666
AC:
15
AN:
225368
Hom.:
0
AF XY:
0.0000160
AC XY:
2
AN XY:
124658
show subpopulations
Gnomad AFR exome
AF:
0.000939
Gnomad AMR exome
AF:
0.0000305
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000179
GnomAD4 exome
AF:
0.0000342
AC:
49
AN:
1433980
Hom.:
0
Cov.:
30
AF XY:
0.0000322
AC XY:
23
AN XY:
714226
show subpopulations
Gnomad4 AFR exome
AF:
0.00125
Gnomad4 AMR exome
AF:
0.0000455
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:
0.00
Gnomad4 OTH exome
AF:
0.0000841
GnomAD4 genome
AF:
0.000421
AC:
64
AN:
151992
Hom.:
0
Cov.:
32
AF XY:
0.000310
AC XY:
23
AN XY:
74244
show subpopulations
Gnomad4 AFR
AF:
0.00150
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000134
Hom.:
0
Bravo
AF:
0.000468
ExAC
AF:
0.0000909
AC:
11

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 02, 2021The c.295G>T (p.A99S) alteration is located in exon 2 (coding exon 1) of the RRAD gene. This alteration results from a G to T substitution at nucleotide position 295, causing the alanine (A) at amino acid position 99 to be replaced by a serine (S). 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
0.087
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.28
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Benign
0.21
T;T
Eigen
Benign
-0.0020
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;.
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.064
T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
0.30
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.66
N;N
REVEL
Benign
0.26
Sift
Uncertain
0.022
D;D
Sift4G
Benign
0.17
T;T
Polyphen
0.28
B;B
Vest4
0.19
MVP
0.79
MPC
1.1
ClinPred
0.11
T
GERP RS
4.2
Varity_R
0.53
gMVP
0.30

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

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

Other links and lift over

dbSNP: rs746648665; hg19: chr16-66958788; API