17-82032785-A-T

Position:

• chr17-82032785-A-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.182A>T​(p.Gln61Leu) 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: 7.01

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, 0.977
• PP5: Variant 17-82032785-A-T is Pathogenic according to our data. Variant chr17-82032785-A-T is described in ClinVar as [Pathogenic, association]. Clinvar id is 585005.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-82032785-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAC3	NM_005052.3	c.182A>T	p.Gln61Leu	missense_variant	3/6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.182A>T	p.Gln61Leu	missense_variant	3/6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.182A>T	p.Gln61Leu	missense_variant	3/6	1	NM_005052.3	ENSP00000304283	P1
RAC3	ENST00000580965.5	c.50A>T	p.Gln17Leu	missense_variant	2/5	2		ENSP00000463590
RAC3	ENST00000584341.1	c.50A>T	p.Gln17Leu	missense_variant	2/5	5		ENSP00000462421

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

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

Aug 03, 2021

- -

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	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.5	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.1	D;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.012	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.81
MutPred		0.85		Loss of disorder (P = 0.0374);.;.;
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.70

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

LitVar

Other links and lift over

dbSNP: rs1568018920; hg19: chr17-79990661;