Genetic Variant RAC1:c.448+141G>C (chr7-6402168-G-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+141G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 1,441,354 control chromosomes in the GnomAD database, including 203,223 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 0.58 ( 27284 hom., cov: 30)

Exomes 𝑓: 0.51 ( 175939 hom. )

Consequence

RAC1
NM_006908.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.580

Publications

15 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=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5 link	c.448+141G>C		intron_variant	Intron 5 of 5	ENST00000348035.9	NP_008839.2	P63000-1A4D2P1
RAC1	NM_018890.4 link	c.505+141G>C		intron_variant	Intron 6 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.448+141G>C		intron_variant	Intron 5 of 5	1	NM_006908.5	ENSP00000258737.7		P63000-1

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88747

AN:

151772

Hom.:

27234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.733

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.631

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.909

Gnomad SAS

AF:

0.639

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.476

Gnomad OTH

AF:

0.555

GnomAD4 exome

AF:

0.512

AC:

660846

AN:

1289464

Hom.:

175939

Cov.:

AF XY:

0.513

AC XY:

326287

AN XY:

636294

show subpopulations

African (AFR)

AF:

0.742

AC:

21484

AN:

28962

American (AMR)

AF:

0.691

AC:

21372

AN:

30942

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

7488

AN:

19898

East Asian (EAS)

AF:

0.907

AC:

34841

AN:

38412

South Asian (SAS)

AF:

0.619

AC:

42822

AN:

69154

European-Finnish (FIN)

AF:

0.534

AC:

23358

AN:

43712

Middle Eastern (MID)

AF:

0.447

AC:

2205

AN:

4928

European-Non Finnish (NFE)

AF:

0.478

AC:

477944

AN:

999600

Other (OTH)

AF:

0.545

AC:

29332

AN:

53856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

14795

29591

44386

59182

73977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14528

29056

43584

58112

72640

<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:

0.585

AC:

88854

AN:

151890

Hom.:

27284

Cov.:

AF XY:

0.592

AC XY:

43937

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.733

AC:

30353

AN:

41406

American (AMR)

AF:

0.632

AC:

9641

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1273

AN:

3472

East Asian (EAS)

AF:

0.909

AC:

4680

AN:

5146

South Asian (SAS)

AF:

0.638

AC:

3071

AN:

4814

European-Finnish (FIN)

AF:

0.545

AC:

5751

AN:

10550

Middle Eastern (MID)

AF:

0.394

AC:

115

AN:

292

European-Non Finnish (NFE)

AF:

0.476

AC:

32316

AN:

67934

Other (OTH)

AF:

0.561

AC:

1184

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1738

3476

5214

6952

8690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.407

Hom.:

1092

Bravo

AF:

0.600

Asia WGS

AF:

0.811

AC:

2818

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.1

(source)

DANN

Benign

0.80

PhyloP100

-0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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