chr12-49992085-T-A

Position:

• chr12-49992085-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001319999.2(RACGAP1):​c.1627A>T​(p.Met543Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RACGAP1 NM_001319999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14462292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RACGAP1	NM_001319999.2	c.1627A>T	p.Met543Leu	missense_variant	15/17	ENST00000312377.10	NP_001306928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RACGAP1	ENST00000312377.10	c.1627A>T	p.Met543Leu	missense_variant	15/17	1	NM_001319999.2	ENSP00000309871.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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

Feb 15, 2023

The c.1627A>T (p.M543L) alteration is located in exon 17 (coding exon 14) of the RACGAP1 gene. This alteration results from a A to T substitution at nucleotide position 1627, causing the methionine (M) at amino acid position 543 to be replaced by a leucine (L). 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	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.67
DEOGEN2	Benign	0.011	T;T;T;T;T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.059
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;.;.;.;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	.;L;L;L;L;L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.50	T;T;T;T;T;T;T
Sift4G	Benign	0.092	T;T;T;T;T;T;.
Polyphen		0.0010	.;B;B;B;B;B;.
Vest4		0.49
MutPred		0.50		.;Gain of catalytic residue at W539 (P = 2e-04);Gain of catalytic residue at W539 (P = 2e-04);Gain of catalytic residue at W539 (P = 2e-04);Gain of catalytic residue at W539 (P = 2e-04);Gain of catalytic residue at W539 (P = 2e-04);.;
MVP		0.34
ClinPred		0.52	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.35

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: chr12-50385868;