Genetic Variant VAV3:p.Glu741Glu (chr1-107596339-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_006113.5(VAV3):c.2223A>G(p.Glu741Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,610,188 control chromosomes in the GnomAD database, including 2,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 214 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2571 hom. )

Consequence

VAV3
NM_006113.5 splice_region, synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

9 publications found

Variant links:

Genes affected

VAV3 (HGNC:12659): (vav guanine nucleotide exchange factor 3) This gene is a member of the VAV gene family. The VAV proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases that activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. This gene product acts as a GEF preferentially for RhoG, RhoA, and to a lesser extent, RAC1, and it associates maximally with the nucleotide-free states of these GTPases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

VAV3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP7

Synonymous conserved (PhyloP=1.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAV3	NM_006113.5 link	c.2223A>G	p.Glu741Glu	splice_region_variant, synonymous_variant	Exon 25 of 27	ENST00000370056.9	NP_006104.4	Q9UKW4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAV3	ENST00000370056.9 link	c.2223A>G	p.Glu741Glu	splice_region_variant, synonymous_variant	Exon 25 of 27	1	NM_006113.5	ENSP00000359073.4		Q9UKW4-1

Frequencies

GnomAD3 genomes

AF:

0.0506

AC:

7691

AN:

152080

Hom.:

216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0416

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0821

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0568

Gnomad FIN

AF:

0.0477

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0609

Gnomad OTH

AF:

0.0526

GnomAD2 exomes

AF:

0.0497

AC:

12287

AN:

247272

AF XY:

0.0517

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.0229

Gnomad ASJ exome

AF:

0.0911

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0477

Gnomad NFE exome

AF:

0.0625

Gnomad OTH exome

AF:

0.0562

GnomAD4 exome

AF:

0.0572

AC:

83444

AN:

1457990

Hom.:

2571

Cov.:

AF XY:

0.0575

AC XY:

41666

AN XY:

725144

show subpopulations

African (AFR)

AF:

0.0406

AC:

1351

AN:

33284

American (AMR)

AF:

0.0247

AC:

1086

AN:

44038

Ashkenazi Jewish (ASJ)

AF:

0.0921

AC:

2387

AN:

25930

East Asian (EAS)

AF:

0.000202

AC:

AN:

39646

South Asian (SAS)

AF:

0.0546

AC:

4659

AN:

85348

European-Finnish (FIN)

AF:

0.0446

AC:

2383

AN:

53382

Middle Eastern (MID)

AF:

0.0908

AC:

523

AN:

5758

European-Non Finnish (NFE)

AF:

0.0611

AC:

67791

AN:

1110382

Other (OTH)

AF:

0.0541

AC:

3256

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3535

7069

10604

14138

17673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2532

5064

7596

10128

12660

<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:

0.0506

AC:

7697

AN:

152198

Hom.:

214

Cov.:

AF XY:

0.0499

AC XY:

3714

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0417

AC:

1734

AN:

41558

American (AMR)

AF:

0.0350

AC:

535

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0821

AC:

285

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0566

AC:

273

AN:

4822

European-Finnish (FIN)

AF:

0.0477

AC:

505

AN:

10598

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0609

AC:

4141

AN:

67970

Other (OTH)

AF:

0.0520

AC:

110

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

384

767

1151

1534

1918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0597

Hom.:

320

Bravo

AF:

0.0489

EpiCase

AF:

0.0615

EpiControl

AF:

0.0628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.2

(source)

DANN

Benign

0.74

PhyloP100

1.0

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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