12-49994283-A-T

Position:

• chr12-49994283-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

The NM_001319999.2(RACGAP1):​c.1187T>A​(p.Leu396Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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)
• Consequence: RACGAP1 NM_001319999.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.24

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 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, 0.929
• PP5: Variant 12-49994283-A-T is Pathogenic according to our data. Variant chr12-49994283-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1344519.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	c.1187T>A	p.Leu396Gln	missense_variant	12/17	ENST00000312377.10	NP_001306928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RACGAP1	ENST00000312377.10	c.1187T>A	p.Leu396Gln	missense_variant	12/17	1	NM_001319999.2	ENSP00000309871.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T;T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.97
MutPred		0.81		Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);.;
MVP		0.82
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs1948102480; hg19: chr12-50388066;