rs764978814

Variant names:

• chr16-66925060-C-T
• rs764978814
• NM_004165.3:c.120G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004165.3(RRAD):​c.120G>A​(p.Met40Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000992 in 1,300,320 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (3 hom.)
• Consequence: RRAD NM_004165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07116127).
• BS2: High AC in GnomAd4 at 9 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.120G>A	p.Met40Ile	missense	Exon 2 of 5	NP_004156.1	P55042
	RRAD	NM_001128850.2		c.120G>A	p.Met40Ile	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.120G>A	p.Met40Ile	missense	Exon 2 of 5	ENSP00000299759.6	P55042
	RRAD	ENST00000889788.1		c.120G>A	p.Met40Ile	missense	Exon 1 of 4	ENSP00000559848.1
	RRAD	ENST00000889790.1		c.120G>A	p.Met40Ile	missense	Exon 2 of 5	ENSP00000559849.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000389 AC: 4 AN: 10288 AF XY: 0.000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 120 AN: 1148294 Hom.: 3 Cov.: 30 AF XY: 0.000134 AC XY: 74 AN XY: 553500

African (AFR) AF: 0.00 AC: 0 AN: 23584

American (AMR) AF: 0.00 AC: 0 AN: 10334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15556

East Asian (EAS) AF: 0.00 AC: 0 AN: 26986

South Asian (SAS) AF: 0.00103 AC: 40 AN: 38684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25392

Middle Eastern (MID) AF: 0.00127 AC: 4 AN: 3154

European-Non Finnish (NFE) AF: 0.0000772 AC: 74 AN: 958200

Other (OTH) AF: 0.0000431 AC: 2 AN: 46404

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000217 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3468

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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.065
Sift	Benign	0.50	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.56
MutPred		0.32		Gain of glycosylation at S39 (P = 0.0391)
MVP		0.64
MPC		1.6
ClinPred		0.16	T
GERP RS		3.4
PromoterAI		-0.047	Neutral
Varity_R		0.55
gMVP		0.42
Mutation Taster		=80/20	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: rs764978814; hg19: chr16-66958963;