Variant 16-66924885-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000299759.11(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. 12/21 in silico tools predict 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
ENST00000299759.11 missense

Scores

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]

RRAD links:

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 GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAD	NM_004165.3 linkuse as main transcript	c.295G>T	p.Ala99Ser	missense_variant	2/5	ENST00000299759.11	NP_004156.1
RRAD	NM_001128850.2 linkuse as main transcript	c.295G>T	p.Ala99Ser	missense_variant	2/5		NP_001122322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RRAD	ENST00000299759.11 linkuse as main transcript	c.295G>T	p.Ala99Ser	missense_variant	2/5	1	NM_004165.3	ENSP00000299759	P1
RRAD	ENST00000566577.1 linkuse as main transcript	c.70G>T	p.Ala24Ser	missense_variant	1/4	5		ENSP00000462559
RRAD	ENST00000568915.5 linkuse as main transcript	c.91G>T	p.Ala31Ser	missense_variant	1/3	5		ENSP00000461995

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

151992

Hom.:

Cov.:

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:

AN:

225368

Hom.:

AF XY:

0.0000160

AC XY:

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:

AN:

1433980

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

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:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

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.:

Bravo

AF:

0.000468

ExAC

AF:

0.0000909

AC:

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 submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The 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

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.0020

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.30

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over