12-47751585-A-G

Position:

• chr12-47751585-A-G

Variant summary

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

The NM_001098531.4(RAPGEF3):​c.381-65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,606,848 control chromosomes in the GnomAD database, including 45,903 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 0.23 (4027 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41876 hom.)
• Consequence: RAPGEF3 NM_001098531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310

Genes affected

RAPGEF3 (HGNC:16629): (Rap guanine nucleotide exchange factor 3) Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including positive regulation of protein modification process; regulation of actin cytoskeleton organization; and regulation of syncytium formation by plasma membrane fusion. Located in filopodium; lamellipodium; and microvillus. Colocalizes with cortical actin cytoskeleton and plasma membrane. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.381-65T>C		intron_variant		ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.381-65T>C		intron_variant		2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.381-65T>C		intron_variant		2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.255-65T>C		intron_variant		5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.255-65T>C		intron_variant		2		ENSP00000448480.1
RAPGEF3	ENST00000395358.7	c.381-65T>C		intron_variant		2		ENSP00000378764.3
RAPGEF3	ENST00000547856.5	n.220-1160T>C		intron_variant		2		ENSP00000449905.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34583 AN: 152122 Hom.: 4026 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.235 AC: 341994 AN: 1454608 Hom.: 41876 Cov.: 37 AF XY: 0.232 AC XY: 167987 AN XY: 722566

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.236

GnomAD4 genome AF: 0.227 AC: 34583 AN: 152240 Hom.: 4027 Cov.: 33 AF XY: 0.220 AC XY: 16401 AN XY: 74436

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.243

Alfa AF: 0.234 Hom.: 4380

Bravo AF: 0.227

Asia WGS AF: 0.129 AC: 446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.58

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: rs2072115; hg19: chr12-48145368; COSMIC: COSV50254897; COSMIC: COSV50254897;