Genetic Variant RAC1:c.226-1540A>G (chr7-6398586-A-G) – 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.226-1540A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,279,172 control chromosomes in the GnomAD database, including 1,524 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 0.036 ( 147 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1377 hom. )

Consequence

RAC1
NM_006908.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.251

Publications

3 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=-0.79).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5 link	c.226-1540A>G		intron_variant	Intron 3 of 5	ENST00000348035.9	NP_008839.2	P63000-1A4D2P1
RAC1	NM_018890.4 link	c.226-76A>G		intron_variant	Intron 3 of 6		NP_061485.1	P63000-2A4D2P0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9 link	c.226-1540A>G		intron_variant	Intron 3 of 5	1	NM_006908.5	ENSP00000258737.7		P63000-1

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

5526

AN:

152190

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00837

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0350

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0196

Gnomad FIN

AF:

0.0439

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0520

Gnomad OTH

AF:

0.0421

GnomAD4 exome

AF:

0.0445

AC:

50160

AN:

1126864

Hom.:

1377

AF XY:

0.0446

AC XY:

25511

AN XY:

571822

show subpopulations

African (AFR)

AF:

0.00724

AC:

183

AN:

25278

American (AMR)

AF:

0.0331

AC:

1205

AN:

36410

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

2707

AN:

23212

East Asian (EAS)

AF:

0.0000833

AC:

AN:

36020

South Asian (SAS)

AF:

0.0217

AC:

1602

AN:

73976

European-Finnish (FIN)

AF:

0.0451

AC:

2338

AN:

51802

Middle Eastern (MID)

AF:

0.0599

AC:

307

AN:

5126

European-Non Finnish (NFE)

AF:

0.0479

AC:

39537

AN:

826058

Other (OTH)

AF:

0.0465

AC:

2278

AN:

48982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2298

4596

6893

9191

11489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1228

2456

3684

4912

6140

<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:

0.0363

AC:

5529

AN:

152308

Hom.:

147

Cov.:

AF XY:

0.0348

AC XY:

2588

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00835

AC:

347

AN:

41574

American (AMR)

AF:

0.0350

AC:

535

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

394

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0199

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0439

AC:

466

AN:

10618

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0520

AC:

3537

AN:

68024

Other (OTH)

AF:

0.0421

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

289

577

866

1154

1443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0415

Hom.:

Bravo

AF:

0.0345

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.91

(source)

DANN

Benign

0.70

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism

(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