7-22202917-T-C

Variant names:

• chr7-22202917-T-C
• rs4719687
• NM_012294.5:c.997-8884A>G

Variant summary

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

The NM_012294.5(RAPGEF5):​c.997-8884A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 364,202 control chromosomes in the GnomAD database, including 48,051 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 0.54 (21808 hom., cov: 32)
  • Exomes 𝑓: 0.49 (26243 hom.)
• Consequence: RAPGEF5 NM_012294.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF5	NM_012294.5	c.997-8884A>G		intron_variant	Intron 9 of 25	ENST00000665637.1	NP_036426.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1	c.997-8884A>G		intron_variant	Intron 9 of 25		NM_012294.5	ENSP00000499535.1

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81351 AN: 151870 Hom.: 21788 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.507

GnomAD3 exomes AF: 0.467 AC: 39993 AN: 85558 Hom.: 9558 AF XY: 0.476 AC XY: 22252 AN XY: 46764

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.507

Gnomad SAS exome AF: 0.448

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.491 AC: 104202 AN: 212214 Hom.: 26243 Cov.: 0 AF XY: 0.494 AC XY: 60967 AN XY: 123422

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.426

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.490

GnomAD4 genome AF: 0.536 AC: 81403 AN: 151988 Hom.: 21808 Cov.: 32 AF XY: 0.534 AC XY: 39668 AN XY: 74292

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.572

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.508

Alfa AF: 0.547 Hom.: 47522

Bravo AF: 0.530

Asia WGS AF: 0.535 AC: 1861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.25
DANN	Benign	0.73

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: rs4719687; hg19: chr7-22242535; COSMIC: COSV59781427;