16-66925060-C-T

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

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]

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAD	NM_004165.3	c.120G>A	p.Met40Ile	missense_variant	Exon 2 of 5	ENST00000299759.11	NP_004156.1
RRAD	NM_001128850.2	c.120G>A	p.Met40Ile	missense_variant	Exon 2 of 5		NP_001122322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAD	ENST00000299759.11	c.120G>A	p.Met40Ile	missense_variant	Exon 2 of 5	1	NM_004165.3	ENSP00000299759.6
RRAD	ENST00000566577.1	c.-109G>A		upstream_gene_variant		5		ENSP00000462559.1
RRAD	ENST00000568915.5	c.-88G>A		upstream_gene_variant		5		ENSP00000461995.1

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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 23584

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 10334

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 15556

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 26986

Gnomad4 SAS exome AF: 0.00103 AC: 40 AN: 38684

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 25392

Gnomad4 NFE exome AF: 0.0000772 AC: 74 AN: 958200

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000413565 AN: 0.000413565

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000103 AC: 0.000102984 AN: 0.000102984

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.120G>A (p.M40I) alteration is located in exon 2 (coding exon 1) of the RRAD gene. This alteration results from a G to A substitution at nucleotide position 120, causing the methionine (M) at amino acid position 40 to be replaced by an isoleucine (I). 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	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;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;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.065
Sift	Benign	0.50	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0010	B;B
Vest4		0.56
MutPred		0.32		Gain of glycosylation at S39 (P = 0.0391);Gain of glycosylation at S39 (P = 0.0391);
MVP		0.64
MPC		1.6
ClinPred		0.16	T
GERP RS		3.4
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

Publications

LitVar

Other links and lift over

dbSNP: rs764978814; hg19: chr16-66958963;