17-82032437-C-T

Position:

• chr17-82032437-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005052.3(RAC3):​c.86C>T​(p.Pro29Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,association (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 NM_005052.3 missense
• Clinical Significance: Pathogenic; association no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 17-82032437-C-T is Pathogenic according to our data. Variant chr17-82032437-C-T is described in ClinVar as [Pathogenic, association]. Clinvar id is 585004.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAC3	NM_005052.3	c.86C>T	p.Pro29Leu	missense_variant	2/6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.86C>T	p.Pro29Leu	missense_variant	2/6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.86C>T	p.Pro29Leu	missense_variant	2/6	1	NM_005052.3	ENSP00000304283.4
RAC3	ENST00000580965	c.-47C>T		5_prime_UTR_variant	1/5	2		ENSP00000463590.1
RAC3	ENST00000584341	c.-87C>T		5_prime_UTR_variant	1/5	5		ENSP00000462421.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic; association

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 08, 2022

- -

Intellectual disability;C4021085:Abnormal brain morphology Other:1

association, no assertion criteria provided

provider interpretation

Costain lab, The Hospital for Sick Children

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.52	P
Vest4		0.87
MutPred		0.80		Loss of glycosylation at T24 (P = 0.157);
MVP		0.91
MPC		1.8
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1568018697; hg19: chr17-79990313;