12-47748853-C-T

Variant names:

• chr12-47748853-C-T
• rs12422983
• NM_001098531.4:c.1120G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.1120G>A	p.Gly374Ser	missense_variant	Exon 11 of 28	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.1120G>A	p.Gly374Ser	missense_variant	Exon 11 of 28	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.1120G>A	p.Gly374Ser	missense_variant	Exon 12 of 29	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.994G>A	p.Gly332Ser	missense_variant	Exon 11 of 28	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.994G>A	p.Gly332Ser	missense_variant	Exon 11 of 27	2		ENSP00000448480.1
RAPGEF3	ENST00000395358.7	c.1120G>A	p.Gly374Ser	missense_variant	Exon 11 of 16	2		ENSP00000378764.3
RAPGEF3	ENST00000495465.6	n.*237G>A		non_coding_transcript_exon_variant	Exon 6 of 9	3		ENSP00000449818.1
RAPGEF3	ENST00000547856.5	n.*428G>A		non_coding_transcript_exon_variant	Exon 7 of 24	2		ENSP00000449905.1
RAPGEF3	ENST00000495465.6	n.*237G>A		3_prime_UTR_variant	Exon 6 of 9	3		ENSP00000449818.1
RAPGEF3	ENST00000547856.5	n.*428G>A		3_prime_UTR_variant	Exon 7 of 24	2		ENSP00000449905.1

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

GnomAD2 exomes AF: 0.119 AC: 29912 AN: 251382 AF XY: 0.120

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 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

African (AFR) AF: 0.105 AC: 3528 AN: 33478

American (AMR) AF: 0.0856 AC: 3827 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5628 AN: 26122

East Asian (EAS) AF: 0.0368 AC: 1460 AN: 39696

South Asian (SAS) AF: 0.0633 AC: 5458 AN: 86248

European-Finnish (FIN) AF: 0.138 AC: 7356 AN: 53418

Middle Eastern (MID) AF: 0.157 AC: 907 AN: 5762

European-Non Finnish (NFE) AF: 0.143 AC: 158692 AN: 1111768

Other (OTH) AF: 0.136 AC: 8210 AN: 60376

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

African (AFR) AF: 0.107 AC: 4460 AN: 41496

American (AMR) AF: 0.125 AC: 1908 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3468

East Asian (EAS) AF: 0.0371 AC: 192 AN: 5176

South Asian (SAS) AF: 0.0633 AC: 305 AN: 4820

European-Finnish (FIN) AF: 0.137 AC: 1454 AN: 10598

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10016 AN: 67958

Other (OTH) AF: 0.137 AC: 290 AN: 2110

Alfa AF: 0.141 Hom.: 6250

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
LIST_S2	Benign	0.76	.;T;.;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;L;.;L
PhyloP100		0.71
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
Mutation Taster		=98/2	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: rs12422983; hg19: chr12-48142636; COSMIC: COSV50200069; COSMIC: COSV50200069;