7-22147337-T-C

Variant names:

• chr7-22147337-T-C
• rs6461639
• NM_012294.5:c.1885-318A>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.1885-318A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 151,994 control chromosomes in the GnomAD database, including 31,518 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 0.64 (31518 hom., cov: 32)
• Consequence: RAPGEF5 NM_012294.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.21
• Publications: 6 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]

ENSG00000305201 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF5	NM_012294.5	MANE Select	c.1885-318A>G		intron	N/A	NP_036426.4
	RAPGEF5	NM_001367600.2		c.976-318A>G		intron	N/A	NP_001354529.1
	RAPGEF5	NM_001367601.1		c.976-318A>G		intron	N/A	NP_001354530.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF5	ENST00000665637.1	MANE Select	c.1885-318A>G		intron	N/A	ENSP00000499535.1
	RAPGEF5	ENST00000401957.6	TSL:1	c.976-318A>G		intron	N/A	ENSP00000384044.1
	RAPGEF5	ENST00000344041.10	TSL:5	c.1426-318A>G		intron	N/A	ENSP00000343656.6

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97745 AN: 151876 Hom.: 31479 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.612

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

GnomAD4 genome AF: 0.644 AC: 97833 AN: 151994 Hom.: 31518 Cov.: 32 AF XY: 0.646 AC XY: 47997 AN XY: 74278

African (AFR) AF: 0.654 AC: 27118 AN: 41452

American (AMR) AF: 0.593 AC: 9062 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3472

East Asian (EAS) AF: 0.748 AC: 3854 AN: 5150

South Asian (SAS) AF: 0.740 AC: 3567 AN: 4818

European-Finnish (FIN) AF: 0.631 AC: 6656 AN: 10546

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43350 AN: 67956

Other (OTH) AF: 0.615 AC: 1299 AN: 2112

Alfa AF: 0.633 Hom.: 91443

Bravo AF: 0.636

Asia WGS AF: 0.745 AC: 2586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-3.2
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: rs6461639; hg19: chr7-22186955;