12-49992604-T-C

Position:

• chr12-49992604-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001319999.2(RACGAP1):​c.1391A>G​(p.Glu464Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RACGAP1 NM_001319999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

RACGAP1 (HGNC:9804): (Rac GTPase activating protein 1) This gene encodes a GTPase-activating protein (GAP) that is a compoment of the centralspindlin complex. This protein binds activated forms of Rho GTPases and stimulates GTP hydrolysis, which results in negative regulation of Rho-mediated signals. This protein plays a regulatory role in cytokinesis, cell growth, and differentiation. Alternatively spliced transcript variants have been found for this gene. There is a pseudogene for this gene on chromosome 12. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RACGAP1	NM_001319999.2	c.1391A>G	p.Glu464Gly	missense_variant	13/17	ENST00000312377.10	NP_001306928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RACGAP1	ENST00000312377.10	c.1391A>G	p.Glu464Gly	missense_variant	13/17	1	NM_001319999.2	ENSP00000309871.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.1391A>G (p.E464G) alteration is located in exon 15 (coding exon 12) of the RACGAP1 gene. This alteration results from a A to G substitution at nucleotide position 1391, causing the glutamic acid (E) at amino acid position 464 to be replaced by a glycine (G). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;.;.;.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.038	D;D;D;D;D;T
Sift4G	Uncertain	0.035	D;D;D;D;D;.
Polyphen		0.20	B;B;B;B;B;.
Vest4		0.51
MutPred		0.45		Gain of catalytic residue at A461 (P = 0.0038);Gain of catalytic residue at A461 (P = 0.0038);Gain of catalytic residue at A461 (P = 0.0038);Gain of catalytic residue at A461 (P = 0.0038);Gain of catalytic residue at A461 (P = 0.0038);.;
MVP		0.32
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-50386387;