7-22144400-A-G

Variant names:

• chr7-22144400-A-G
• rs1859805
• NM_012294.5:c.2186+644T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012294.5(RAPGEF5):​c.2186+644T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 152,080 control chromosomes in the GnomAD database, including 15,416 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 0.45 (15416 hom., cov: 33)
• Consequence: RAPGEF5 NM_012294.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.513 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.2186+644T>C		intron	N/A	NP_036426.4
	RAPGEF5	NM_001367600.2		c.1277+644T>C		intron	N/A	NP_001354529.1	Q92565-1
	RAPGEF5	NM_001367601.1		c.1277+644T>C		intron	N/A	NP_001354530.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF5	ENST00000665637.1	MANE Select	c.2186+644T>C		intron	N/A	ENSP00000499535.1	A0A590UJR0
	RAPGEF5	ENST00000401957.6	TSL:1	c.1277+644T>C		intron	N/A	ENSP00000384044.1	Q92565-1
	RAPGEF5	ENST00000344041.10	TSL:5	c.1727+644T>C		intron	N/A	ENSP00000343656.6	A8MQ07

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68127 AN: 151962 Hom.: 15414 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.448 AC: 68150 AN: 152080 Hom.: 15416 Cov.: 33 AF XY: 0.449 AC XY: 33350 AN XY: 74320

African (AFR) AF: 0.399 AC: 16563 AN: 41478

American (AMR) AF: 0.426 AC: 6511 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1474 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1918 AN: 5160

South Asian (SAS) AF: 0.530 AC: 2554 AN: 4820

European-Finnish (FIN) AF: 0.445 AC: 4704 AN: 10562

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32981 AN: 67992

Other (OTH) AF: 0.434 AC: 914 AN: 2108

Alfa AF: 0.461 Hom.: 20096

Bravo AF: 0.440

Asia WGS AF: 0.462 AC: 1605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		0.065
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: rs1859805; hg19: chr7-22184018;