17-82032997-T-A

Variant names:

• chr17-82032997-T-A
• NM_005052.3:c.276T>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005052.3(RAC3):​c.276T>A​(p.Asn92Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 NM_005052.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.125

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 Pathogenic. Variant got 10 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, 0.972
• PP5: Variant 17-82032997-T-A is Pathogenic according to our data. Variant chr17-82032997-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2663816.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAC3	NM_005052.3	c.276T>A	p.Asn92Lys	missense_variant	Exon 4 of 6	ENST00000306897.9	NP_005043.1
RAC3	NM_001316307.2	c.276T>A	p.Asn92Lys	missense_variant	Exon 4 of 6		NP_001303236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAC3	ENST00000306897.9	c.276T>A	p.Asn92Lys	missense_variant	Exon 4 of 6	1	NM_005052.3	ENSP00000304283.4
RAC3	ENST00000580965.5	c.144T>A	p.Asn48Lys	missense_variant	Exon 3 of 5	2		ENSP00000463590.1
RAC3	ENST00000584341.1	c.144T>A	p.Asn48Lys	missense_variant	Exon 3 of 5	5		ENSP00000462421.1
RAC3	ENST00000585014.1	n.120T>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 13, 2022

Centre de Genetique Humaine, Institut de Pathologie et de Genetique

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variant not found in GnomAD database, affecting a highly conserved amino acid (down to C. Elegans) in the "small GTPase domain". In silico tools classify the variant as pathogenic (SIFT, PolyPhen2, CADD score 20.5). The variant was not observed in the parents of the affected foetus (maternity & paternity were confirmed) suggesting de novo variant. The first clinical suspicion was raised at 22 weeks of gestation. Based on ultrasound + foetal MRI the foetus exhibited multiple CNS malformations (see dedicated section). Foetopathology described facial dysmorphism (see dedicated section). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	D;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.92	P;.;.
Vest4		0.88
MutPred		0.91		Gain of methylation at N92 (P = 0.0157);.;.;
MVP		0.87
MPC		1.7
ClinPred		1.0	D
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-79990873;