Genetic Variant RRAD:p.Arg129His (chr16-66923904-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004165.3(RRAD):c.386G>A(p.Arg129His) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RRAD
NM_004165.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAD	NM_004165.3 link	c.386G>A	p.Arg129His	missense_variant	Exon 3 of 5	ENST00000299759.11	NP_004156.1	P55042A0A024R6X0
RRAD	NM_001128850.2 link	c.386G>A	p.Arg129His	missense_variant	Exon 3 of 5		NP_001122322.1	P55042A0A024R6X0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RRAD	ENST00000299759.11 link	c.386G>A	p.Arg129His	missense_variant	Exon 3 of 5	1	NM_004165.3	ENSP00000299759.6	P55042
RRAD	ENST00000566577.1 link	c.158G>A	p.Arg53His	missense_variant	Exon 2 of 4	5		ENSP00000462559.1	J3KSM6
RRAD	ENST00000568915.5 link	c.179G>A	p.Arg60His	missense_variant	Exon 2 of 3	5		ENSP00000461995.1	J3KRG9
RRAD	ENST00000567791.1 link	n.-6G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386G>A (p.R129H) alteration is located in exon 3 (coding exon 2) of the RRAD gene. This alteration results from a G to A substitution at nucleotide position 386, causing the arginine (R) at amino acid position 129 to be replaced by a histidine (H). 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

0.26

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D

Eigen

Benign

0.15

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.38

B;B

Vest4

0.84

MutPred

0.57

Gain of glycosylation at T126 (P = 0.0554);Gain of glycosylation at T126 (P = 0.0554);

MVP

0.88

MPC

1.0

ClinPred

0.98

GERP RS

4.1

Varity_R

0.41

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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