Genetic Variant RAC3:p.Pro87Leu (chr17-82032981-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PP3_ModerateBS2

The NM_005052.3(RAC3):c.260C>T(p.Pro87Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RAC3
NM_005052.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

Variant links:

Genes affected

RAC3 (HGNC:9803): (Rac family small GTPase 3) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

RAC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Ras-related C3 botulinum toxin substrate 3 (size 188) in uniprot entity RAC3_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_005052.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC3	NM_005052.3 link	c.260C>T	p.Pro87Leu	missense_variant	Exon 4 of 6	ENST00000306897.9	NP_005043.1	P60763
RAC3	NM_001316307.2 link	c.260C>T	p.Pro87Leu	missense_variant	Exon 4 of 6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAC3	ENST00000306897.9 link	c.260C>T	p.Pro87Leu	missense_variant	Exon 4 of 6	1	NM_005052.3	ENSP00000304283.4	P60763
RAC3	ENST00000580965.5 link	c.128C>T	p.Pro43Leu	missense_variant	Exon 3 of 5	2		ENSP00000463590.1	J3QLK0
RAC3	ENST00000584341.1 link	c.128C>T	p.Pro43Leu	missense_variant	Exon 3 of 5	5		ENSP00000462421.1	J3KSC4
RAC3	ENST00000585014.1 link	n.104C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250698

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000249

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461272

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260C>T (p.P87L) alteration is located in exon 4 (coding exon 4) of the RAC3 gene. This alteration results from a C to T substitution at nucleotide position 260, causing the proline (P) at amino acid position 87 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

2.0e-7

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

-0.015

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-9.0

D;.;.

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.72

P;.;.

Vest4

0.91

MutPred

0.53

Loss of loop (P = 0.1242);.;.;

MVP

0.93

MPC

1.3

ClinPred

0.62

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over