chr12-47748853-C-T

Position:

• chr12-47748853-C-T

Variant summary

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

The NM_001098531.4(RAPGEF3):​c.1120G>A​(p.Gly374Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,710 control chromosomes in the GnomAD database, including 15,389 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1336 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14053 hom.)
• Consequence: RAPGEF3 NM_001098531.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.711

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014111698).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF3	NM_001098531.4	c.1120G>A	p.Gly374Ser	missense_variant	11/28	ENST00000449771.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.1120G>A	p.Gly374Ser	missense_variant	11/28	2	NM_001098531.4	P4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19517 AN: 152012 Hom.: 1334 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.119 AC: 29912 AN: 251382 Hom.: 2168 AF XY: 0.120 AC XY: 16259 AN XY: 135866

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0804

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0361

Gnomad SAS exome AF: 0.0635

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.133 AC: 195066 AN: 1461580 Hom.: 14053 Cov.: 33 AF XY: 0.132 AC XY: 96257 AN XY: 727102

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0856

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.0368

Gnomad4 SAS exome AF: 0.0633

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.128 AC: 19522 AN: 152130 Hom.: 1336 Cov.: 32 AF XY: 0.127 AC XY: 9446 AN XY: 74358

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.0633

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.137

Alfa AF: 0.143 Hom.: 3456

Bravo AF: 0.127

TwinsUK AF: 0.141 AC: 524

ALSPAC AF: 0.143 AC: 552

ESP6500AA AF: 0.111 AC: 488

ESP6500EA AF: 0.146 AC: 1253

ExAC AF: 0.117 AC: 14228

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.;.;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.018	N
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;L;.;L
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.076	T;D;D;T;D;T
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.99	D;.;.;D;.;.
Vest4		0.058
MPC		0.21
ClinPred		0.0074	T
GERP RS		3.3
Varity_R		0.044
gMVP		0.27

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: rs12422983; hg19: chr12-48142636; COSMIC: COSV50200069; COSMIC: COSV50200069;