Variant 12-49994176-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM2PP3_ModeratePP5

The NM_001319999.2(RACGAP1):c.1294C>T(p.Pro432Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RACGAP1
NM_001319999.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 9.91

Variant links:

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]

RACGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS1

Transcript NM_001319999.2 (RACGAP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 12-49994176-G-A is Pathogenic according to our data. Variant chr12-49994176-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1344520.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RACGAP1	NM_001319999.2 linkuse as main transcript	c.1294C>T	p.Pro432Ser	missense_variant	12/17	ENST00000312377.10	NP_001306928.1	Q9H0H5A0A024R136

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RACGAP1	ENST00000312377.10 linkuse as main transcript	c.1294C>T	p.Pro432Ser	missense_variant	12/17	1	NM_001319999.2	ENSP00000309871.5		Q9H0H5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Anemia, congenital dyserythropoietic, type IIIb, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

research

BloodGenetics

Jul 04, 2022

- -

Anemia, congenital dyserythropoietic, type IIIb

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T;T;T;T;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;.;.;.;D;D

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.8

M;M;M;M;M;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.5

D;D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D;.

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.91

MutPred

0.78

Gain of MoRF binding (P = 0.0415);Gain of MoRF binding (P = 0.0415);Gain of MoRF binding (P = 0.0415);Gain of MoRF binding (P = 0.0415);Gain of MoRF binding (P = 0.0415);.;

MVP

0.70

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over