rs17146521

Positions:

• chr7-22278040-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012294.5(RAPGEF5):​c.748-11028T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,116 control chromosomes in the GnomAD database, including 1,026 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1026 hom., cov: 32)
• Consequence: RAPGEF5 NM_012294.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182

Genes affected

RAPGEF5 (HGNC:16862): (Rap guanine nucleotide exchange factor 5) Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF5, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000 [PubMed 10934204]).[supplied by OMIM, Mar 2008]

RAPGEF5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF5	NM_012294.5	c.748-11028T>G		intron_variant		ENST00000665637.1	NP_036426.4
RAPGEF5	XM_017012837.3	c.373-11028T>G		intron_variant			XP_016868326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1	c.748-11028T>G		intron_variant			NM_012294.5	ENSP00000499535.1
RAPGEF5	ENST00000405243.1	c.748-11028T>G		intron_variant		1		ENSP00000384870.1
RAPGEF5	ENST00000344041.10	c.289-11028T>G		intron_variant		5		ENSP00000343656.6
RAPGEF5	ENST00000475788.1	n.68-11028T>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15190 AN: 151998 Hom.: 1022 Cov.: 32

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.0871

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.100 AC: 15236 AN: 152116 Hom.: 1026 Cov.: 32 AF XY: 0.107 AC XY: 7957 AN XY: 74356

Gnomad4 AFR AF: 0.0712

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.0732

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.0855

Gnomad4 OTH AF: 0.0919

Alfa AF: 0.0882 Hom.: 1443

Bravo AF: 0.0901

Asia WGS AF: 0.245 AC: 848 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.56

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: rs17146521; hg19: chr7-22317659;