NM_004165.3:c.295G>T

Variant names:

• chr16-66924885-C-A
• rs746648665
• NM_004165.3:c.295G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 13/22 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 NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06434655).
• BS2: High AC in GnomAd4 at 64 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004165.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAD	NM_004165.3	MANE Select	c.295G>T	p.Ala99Ser	missense	Exon 2 of 5	NP_004156.1	P55042
	RRAD	NM_001128850.2		c.295G>T	p.Ala99Ser	missense	Exon 2 of 5	NP_001122322.1	P55042

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAD	ENST00000299759.11	TSL:1 MANE Select	c.295G>T	p.Ala99Ser	missense	Exon 2 of 5	ENSP00000299759.6	P55042
	RRAD	ENST00000889788.1		c.295G>T	p.Ala99Ser	missense	Exon 1 of 4	ENSP00000559848.1
	RRAD	ENST00000889790.1		c.295G>T	p.Ala99Ser	missense	Exon 2 of 5	ENSP00000559849.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 151992 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000666 AC: 15 AN: 225368 AF XY: 0.0000160

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 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

African (AFR) AF: 0.00125 AC: 41 AN: 32924

American (AMR) AF: 0.0000455 AC: 2 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25800

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 84706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39466

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103014

Other (OTH) AF: 0.0000841 AC: 5 AN: 59468

GnomAD4 genome AF: 0.000421 AC: 64 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74244

African (AFR) AF: 0.00150 AC: 62 AN: 41416

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000468

ExAC AF: 0.0000909 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.30	N
PhyloP100		7.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.26
Sift	Uncertain	0.022	D
Sift4G	Benign	0.17	T
Polyphen		0.28	B
Vest4		0.19
MVP		0.79
MPC		1.1
ClinPred		0.11	T
GERP RS		4.2
PromoterAI		0.021	Neutral
Varity_R		0.53
gMVP		0.30
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs746648665; hg19: chr16-66958788;