9-131584333-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001377935.1(RAPGEF1):c.3392A>C(p.Glu1131Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1131G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPGEF1 NM_001377935.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

RAPGEF1 (HGNC:4568): (Rap guanine nucleotide exchange factor 1) This gene encodes a human guanine nucleotide exchange factor. It transduces signals from CRK by binding the SH3 domain of CRK, and activating several members of the Ras family of GTPases. This signaling cascade that may be involved in apoptosis, integrin-mediated signal transduction, and cell transformation. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RAPGEF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF1	NM_001377935.1	c.3392A>C	p.Glu1131Ala	missense_variant	24/27	ENST00000683357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.3392A>C	p.Glu1131Ala	missense_variant	24/27		NM_001377935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Mar 01, 2023

The c.2888A>C (p.E963A) alteration is located in exon 21 (coding exon 21) of the RAPGEF1 gene. This alteration results from a A to C substitution at nucleotide position 2888, causing the glutamic acid (E) at amino acid position 963 to be replaced by an alanine (A). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.79
MutPred		0.59		Gain of catalytic residue at E945 (P = 0.0082);.;.;
MVP		0.76
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.57
gMVP		0.67

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: chr9-134459720;