7-22202917-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012294.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF5	NM_012294.5	MANE Select	c.997-8884A>G		intron	N/A	NP_036426.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF5	ENST00000665637.1	MANE Select	c.997-8884A>G		intron	N/A	ENSP00000499535.1	A0A590UJR0
	RAPGEF5	ENST00000405243.1	TSL:1	c.997-8884A>G		intron	N/A	ENSP00000384870.1	E9PGY3
	RAPGEF5	ENST00000344041.10	TSL:5	c.538-8884A>G		intron	N/A	ENSP00000343656.6	A8MQ07

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

GnomAD2 exomes AF: 0.467 AC: 39993 AN: 85558 AF XY: 0.476

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 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

African (AFR) AF: 0.463 AC: 2508 AN: 5422

American (AMR) AF: 0.353 AC: 5263 AN: 14926

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 2993 AN: 7032

East Asian (EAS) AF: 0.509 AC: 3225 AN: 6332

South Asian (SAS) AF: 0.474 AC: 20616 AN: 43508

European-Finnish (FIN) AF: 0.504 AC: 4997 AN: 9914

Middle Eastern (MID) AF: 0.348 AC: 846 AN: 2432

European-Non Finnish (NFE) AF: 0.522 AC: 58896 AN: 112736

Other (OTH) AF: 0.490 AC: 4858 AN: 9912

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

African (AFR) AF: 0.525 AC: 21736 AN: 41424

American (AMR) AF: 0.463 AC: 7071 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1654 AN: 3470

East Asian (EAS) AF: 0.572 AC: 2958 AN: 5170

South Asian (SAS) AF: 0.511 AC: 2463 AN: 4816

European-Finnish (FIN) AF: 0.539 AC: 5691 AN: 10550

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38079 AN: 67954

Other (OTH) AF: 0.508 AC: 1075 AN: 2116

Alfa AF: 0.548 Hom.: 98070

Bravo AF: 0.530

Asia WGS AF: 0.535 AC: 1861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.25
DANN	Benign	0.73
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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