Genetic Variant RAC1:c.448+30T>C (chr7-6402057-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006908.5(RAC1):c.448+30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,602,402 control chromosomes in the GnomAD database, including 10,798 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.076 ( 1082 hom., cov: 32)

Exomes 𝑓: 0.071 ( 9716 hom. )

Consequence

RAC1
NM_006908.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.383

Publications

8 publications found

Variant links:

Genes affected

RAC1 (HGNC:9801): (Rac family small GTPase 1) The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

RAC1 Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 48
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Illumina, Ambry Genetics

RAC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5 link	c.448+30T>C		intron_variant	Intron 5 of 5	ENST00000348035.9	NP_008839.2
RAC1	NM_018890.4 link	c.505+30T>C		intron_variant	Intron 6 of 6		NP_061485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9 link	c.448+30T>C		intron_variant	Intron 5 of 5	1	NM_006908.5	ENSP00000258737.7

Frequencies

GnomAD3 genomes

AF:

0.0759

AC:

11545

AN:

152020

Hom.:

1081

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0286

Gnomad AMI

AF:

0.176

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0738

Gnomad EAS

AF:

0.506

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0462

Gnomad OTH

AF:

0.0825

GnomAD2 exomes

AF:

0.117

AC:

28087

AN:

240192

AF XY:

0.117

show subpopulations

Gnomad AFR exome

AF:

0.0267

Gnomad AMR exome

AF:

0.116

Gnomad ASJ exome

AF:

0.0721

Gnomad EAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.0475

Gnomad OTH exome

AF:

0.0924

GnomAD4 exome

AF:

0.0710

AC:

103017

AN:

1450264

Hom.:

9716

Cov.:

AF XY:

0.0744

AC XY:

53609

AN XY:

720910

show subpopulations

African (AFR)

AF:

0.0267

AC:

887

AN:

33208

American (AMR)

AF:

0.113

AC:

4926

AN:

43642

Ashkenazi Jewish (ASJ)

AF:

0.0716

AC:

1804

AN:

25178

East Asian (EAS)

AF:

0.542

AC:

21440

AN:

39584

South Asian (SAS)

AF:

0.194

AC:

16355

AN:

84444

European-Finnish (FIN)

AF:

0.105

AC:

5545

AN:

52786

Middle Eastern (MID)

AF:

0.0577

AC:

328

AN:

5684

European-Non Finnish (NFE)

AF:

0.0422

AC:

46698

AN:

1105826

Other (OTH)

AF:

0.0840

AC:

5034

AN:

59912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3899

7798

11698

15597

19496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2060

4120

6180

8240

10300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0759

AC:

11549

AN:

152138

Hom.:

1082

Cov.:

AF XY:

0.0857

AC XY:

6369

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0287

AC:

1191

AN:

41554

American (AMR)

AF:

0.115

AC:

1760

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0738

AC:

256

AN:

3470

East Asian (EAS)

AF:

0.506

AC:

2601

AN:

5140

South Asian (SAS)

AF:

0.213

AC:

1024

AN:

4814

European-Finnish (FIN)

AF:

0.115

AC:

1219

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0462

AC:

3144

AN:

67984

Other (OTH)

AF:

0.0873

AC:

184

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

474

947

1421

1894

2368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0542

Hom.:

100

Bravo

AF:

0.0708

Asia WGS

AF:

0.356

AC:

1236

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.8

(source)

DANN

Benign

0.74

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over