9-131587996-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001377935.1(RAPGEF1):c.3084T>G(p.His1028Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAPGEF1 NM_001377935.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.449

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RAPGEF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.40004733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF1	NM_001377935.1	c.3084T>G	p.His1028Gln	missense_variant	21/27	ENST00000683357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF1	ENST00000683357.1	c.3084T>G	p.His1028Gln	missense_variant	21/27		NM_001377935.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152166 Hom.: 0 Cov.: 34 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00277 AC: 3985 AN: 1440650 Hom.: 0 Cov.: 33 AF XY: 0.00252 AC XY: 1811 AN XY: 717304

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000810

Gnomad4 EAS exome AF: 0.000355

Gnomad4 SAS exome AF: 0.000863

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.00333

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152284 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Jun 24, 2022

The c.2580T>G (p.H860Q) alteration is located in exon 18 (coding exon 18) of the RAPGEF1 gene. This alteration results from a T to G substitution at nucleotide position 2580, causing the histidine (H) at amino acid position 860 to be replaced by a glutamine (Q). 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	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.16	B;.;B
Vest4		0.62
MutPred		0.43		Loss of disorder (P = 0.1163);.;.;
MVP		0.71
MPC		1.7
ClinPred		0.57	D
GERP RS		-1.0
Varity_R		0.18
gMVP		0.39

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: chr9-134463383;