rs1379395211

Variant names:

• chr17-82032779-C-G
• rs1379395211
• NM_005052.3:c.176C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-82032779-C-G
• chr17-82032779-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_005052.3(RAC3):​c.176C>G​(p.Ala59Gly) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAC3 NM_005052.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 5.82
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with structural brain anomalies and dysmorphic facies

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005052.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 17-82032779-C-G is Pathogenic according to our data. Variant chr17-82032779-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488059.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005052.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC3	NM_005052.3	MANE Select	c.176C>G	p.Ala59Gly	missense	Exon 3 of 6	NP_005043.1	P60763
	RAC3	NM_001316307.2		c.176C>G	p.Ala59Gly	missense	Exon 3 of 6	NP_001303236.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC3	ENST00000306897.9	TSL:1 MANE Select	c.176C>G	p.Ala59Gly	missense	Exon 3 of 6	ENSP00000304283.4	P60763
	RAC3	ENST00000924839.1		c.455C>G	p.Ala152Gly	missense	Exon 3 of 6	ENSP00000594898.1
	RAC3	ENST00000924841.1		c.176C>G	p.Ala59Gly	missense	Exon 3 of 6	ENSP00000594900.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (5)
1	-	-	Distal shortening of limbs (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.57	P
Vest4		0.76
MutPred		0.68		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.92

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

Other links and lift over

dbSNP: rs1379395211; hg19: chr17-79990655;