Genetic Variant RAPGEF3:c.2049+3A>G (chr12-47740912-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Variant links:

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 links:

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

RPAP3-DT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 link	c.2049+3A>G		splice_region_variant, intron_variant	Intron 20 of 27	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 link	c.2049+3A>G	splice_region_variant, intron_variant	Intron 20 of 27	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 link	c.2049+3A>G	splice_region_variant, intron_variant	Intron 21 of 28	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 link	c.1923+3A>G	splice_region_variant, intron_variant	Intron 20 of 27	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 link	c.1776+3A>G	splice_region_variant, intron_variant	Intron 19 of 26	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 link	n.*1357+3A>G	splice_region_variant, intron_variant	Intron 16 of 23	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.538

AC:

81805

AN:

152022

Hom.:

22125

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.522

AC:

129198

AN:

247578

Hom.:

34842

AF XY:

0.533

AC XY:

71462

AN XY:

134198

show subpopulations

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 SAS exome

AF:

0.552

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.:

AF XY:

0.553

AC XY:

401843

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.517

Gnomad4 AMR exome

AF:

0.368

Gnomad4 ASJ exome

AF:

0.623

Gnomad4 EAS exome

AF:

0.468

Gnomad4 SAS exome

AF:

0.557

Gnomad4 FIN exome

AF:

0.552

Gnomad4 NFE exome

AF:

0.559

Gnomad4 OTH exome

AF:

0.564

GnomAD4 genome

AF:

0.538

AC:

81829

AN:

152140

Hom.:

22126

Cov.:

AF XY:

0.538

AC XY:

40020

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.518

Gnomad4 AMR

AF:

0.484

Gnomad4 ASJ

AF:

0.617

Gnomad4 EAS

AF:

0.455

Gnomad4 SAS

AF:

0.549

Gnomad4 FIN

AF:

0.563

Gnomad4 NFE

AF:

0.559

Gnomad4 OTH

AF:

0.562

Alfa

AF:

0.552

Hom.:

40259

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.5

DANN

Benign

0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over