9-131592175-A-C

Variant names:

• chr9-131592175-A-C
• rs992772220
• NM_001377935.1:c.2698T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377935.1(RAPGEF1):​c.2698T>G​(p.Leu900Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000961 in 1,561,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RAPGEF1 NM_001377935.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19732702).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF1	NM_001377935.1	c.2698T>G	p.Leu900Val	missense_variant	Exon 18 of 27	ENST00000683357.1	NP_001364864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.2698T>G	p.Leu900Val	missense_variant	Exon 18 of 27		NM_001377935.1	ENSP00000508246.1
RAPGEF1	ENST00000372189.7	c.2140T>G	p.Leu714Val	missense_variant	Exon 15 of 24	1		ENSP00000361263.2

Frequencies

GnomAD3 genomes AF: 0.0000578 AC: 6 AN: 103718 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000206

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1457664 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725368

African (AFR) AF: 0.000210 AC: 7 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108260

Other (OTH) AF: 0.0000166 AC: 1 AN: 60240

GnomAD4 genome AF: 0.0000578 AC: 6 AN: 103718 Hom.: 0 Cov.: 33 AF XY: 0.0000609 AC XY: 3 AN XY: 49260

African (AFR) AF: 0.000177 AC: 5 AN: 28264

American (AMR) AF: 0.00 AC: 0 AN: 9336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3666

South Asian (SAS) AF: 0.00 AC: 0 AN: 2778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000206 AC: 1 AN: 48588

Other (OTH) AF: 0.00 AC: 0 AN: 1362

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2194T>G (p.L732V) alteration is located in exon 15 (coding exon 15) of the RAPGEF1 gene. This alteration results from a T to G substitution at nucleotide position 2194, causing the leucine (L) at amino acid position 732 to be replaced by a valine (V). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		1.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.27
MutPred		0.54		.;Loss of ubiquitination at K727 (P = 0.077);.;
MVP		0.52
MPC		1.1
ClinPred		0.18	T
GERP RS		-2.2
Varity_R		0.087
gMVP		0.67
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs992772220; hg19: chr9-134467562;