12-47740912-T-C

Variant names:

• chr12-47740912-T-C
• rs2074533
• NM_001098531.4:c.2049+3A>G

Variant summary

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

The NM_001098531.4(RAPGEF3):​c.2049+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,613,440 control chromosomes in the GnomAD database, including 246,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (22126 hom., cov: 34)
  • Exomes 𝑓: 0.55 (224259 hom.)
• Consequence: RAPGEF3 NM_001098531.4 splice_region, intron
• Scores: Splicing: ADA: 0.06071
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 17 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]

RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098531.4. 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
	RAPGEF3	NM_001098531.4	MANE Select	c.2049+3A>G		splice_region intron	N/A	NP_001092001.2
	RAPGEF3	NM_001098532.2		c.1923+3A>G		splice_region intron	N/A	NP_001092002.1
	RAPGEF3	NM_006105.5		c.1923+3A>G		splice_region intron	N/A	NP_006096.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF3	ENST00000449771.7	TSL:2 MANE Select	c.2049+3A>G		splice_region intron	N/A	ENSP00000395708.2
	RAPGEF3	ENST00000389212.7	TSL:2	c.2049+3A>G		splice_region intron	N/A	ENSP00000373864.3
	RAPGEF3	ENST00000549151.5	TSL:5	c.1923+3A>G		splice_region intron	N/A	ENSP00000448619.1

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81805 AN: 152022 Hom.: 22125 Cov.: 34

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.522 AC: 129198 AN: 247578 AF XY: 0.533

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.561

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.551 AC: 805428 AN: 1461300 Hom.: 224259 Cov.: 82 AF XY: 0.553 AC XY: 401843 AN XY: 726946

African (AFR) AF: 0.517 AC: 17313 AN: 33474

American (AMR) AF: 0.368 AC: 16417 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16279 AN: 26124

East Asian (EAS) AF: 0.468 AC: 18559 AN: 39682

South Asian (SAS) AF: 0.557 AC: 48030 AN: 86222

European-Finnish (FIN) AF: 0.552 AC: 29365 AN: 53220

Middle Eastern (MID) AF: 0.669 AC: 3858 AN: 5764

European-Non Finnish (NFE) AF: 0.559 AC: 621542 AN: 1111778

Other (OTH) AF: 0.564 AC: 34065 AN: 60380

GnomAD4 genome AF: 0.538 AC: 81829 AN: 152140 Hom.: 22126 Cov.: 34 AF XY: 0.538 AC XY: 40020 AN XY: 74380

African (AFR) AF: 0.518 AC: 21493 AN: 41496

American (AMR) AF: 0.484 AC: 7407 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2142 AN: 3470

East Asian (EAS) AF: 0.455 AC: 2351 AN: 5166

South Asian (SAS) AF: 0.549 AC: 2652 AN: 4828

European-Finnish (FIN) AF: 0.563 AC: 5971 AN: 10606

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 38000 AN: 67958

Other (OTH) AF: 0.562 AC: 1186 AN: 2112

Alfa AF: 0.549 Hom.: 57768

Bravo AF: 0.529

Asia WGS AF: 0.475 AC: 1656 AN: 3478

EpiCase AF: 0.580

EpiControl AF: 0.576

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.5
DANN	Benign	0.57
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.061
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2074533; hg19: chr12-48134695; COSMIC: COSV50198991; COSMIC: COSV50198991;