Genetic Variant NM_006908.5:c.-289G>C (chr7-6374447-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.-289G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 158,262 control chromosomes in the GnomAD database, including 1,177 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 0.078 ( 1105 hom., cov: 32)

Exomes 𝑓: 0.070 ( 72 hom. )

Consequence

RAC1
NM_006908.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.123

Publications

10 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=-0.48).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC1	NM_006908.5 link	c.-289G>C		upstream_gene_variant		ENST00000348035.9	NP_008839.2	P63000-1A4D2P1
RAC1	NM_018890.4 link	c.-289G>C		upstream_gene_variant			NP_061485.1	P63000-2A4D2P0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC1	ENST00000348035.9 link	c.-289G>C		upstream_gene_variant		1	NM_006908.5	ENSP00000258737.7		P63000-1

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11846

AN:

151490

Hom.:

1096

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0865

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0640

Gnomad EAS

AF:

0.503

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.0920

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0745

GnomAD4 exome

AF:

0.0698

AC:

465

AN:

6664

Hom.:

AF XY:

0.0639

AC XY:

239

AN XY:

3740

show subpopulations

African (AFR)

AF:

0.0588

AC:

AN:

170

American (AMR)

AF:

0.0960

AC:

AN:

198

Ashkenazi Jewish (ASJ)

AF:

0.0505

AC:

AN:

218

East Asian (EAS)

AF:

0.524

AC:

238

AN:

454

South Asian (SAS)

AF:

0.130

AC:

AN:

292

European-Finnish (FIN)

AF:

0.0681

AC:

AN:

382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0210

AC:

AN:

4518

Other (OTH)

AF:

0.0697

AC:

AN:

402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0784

AC:

11882

AN:

151598

Hom.:

1105

Cov.:

AF XY:

0.0879

AC XY:

6512

AN XY:

74094

show subpopulations

African (AFR)

AF:

0.0872

AC:

3613

AN:

41422

American (AMR)

AF:

0.105

AC:

1604

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0640

AC:

222

AN:

3468

East Asian (EAS)

AF:

0.504

AC:

2563

AN:

5090

South Asian (SAS)

AF:

0.205

AC:

987

AN:

4818

European-Finnish (FIN)

AF:

0.0920

AC:

959

AN:

10422

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0258

AC:

1754

AN:

67856

Other (OTH)

AF:

0.0794

AC:

167

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

503

1006

1509

2012

2515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0475

Hom.:

Bravo

AF:

0.0755

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.12

PromoterAI

-0.019

Neutral

(source)

Splicing

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