9-131621833-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001377935.1(RAPGEF1):c.1868C>G(p.Ala623Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAPGEF1 NM_001377935.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RAPGEF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.21212894).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF1	NM_001377935.1	c.1868C>G	p.Ala623Gly	missense_variant	11/27	ENST00000683357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.1868C>G	p.Ala623Gly	missense_variant	11/27		NM_001377935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000249 AC: 6 AN: 241096 Hom.: 0 AF XY: 0.0000305 AC XY: 4 AN XY: 130994

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000179

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: 6 AN: 1458100 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 4 AN XY: 724976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000136

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

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 28, 2024

The c.1871C>G (p.A624G) alteration is located in exon 11 (coding exon 11) of the RAPGEF1 gene. This alteration results from a C to G substitution at nucleotide position 1871, causing the alanine (A) at amino acid position 624 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	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.098
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.86	P;.;P
Vest4		0.27
MutPred		0.17		.;Gain of relative solvent accessibility (P = 0.1259);.;
MVP		0.47
MPC		0.73
ClinPred		0.43	T
GERP RS		5.6
Varity_R		0.10
gMVP		0.22

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: rs754884637; hg19: chr9-134497220;