7-22144400-A-G

Position:

• chr7-22144400-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF5	NM_012294.5	c.2186+644T>C		intron_variant		ENST00000665637.1	NP_036426.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1	c.2186+644T>C		intron_variant			NM_012294.5	ENSP00000499535.1
RAPGEF5	ENST00000401957.6	c.1277+644T>C		intron_variant		1		ENSP00000384044.1
RAPGEF5	ENST00000344041.10	c.1727+644T>C		intron_variant		5		ENSP00000343656.6
RAPGEF5	ENST00000468825.1	n.223+644T>C		intron_variant		3

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

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.434

Alfa AF: 0.464 Hom.: 15275

Bravo AF: 0.440

Asia WGS AF: 0.462 AC: 1605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.61

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: rs1859805; hg19: chr7-22184018;