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GeneBe

12-47737684-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001098531.4(RAPGEF3):c.2655C>T(p.Cys885=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000864 in 1,612,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00087 ( 1 hom. )

Consequence

RAPGEF3
NM_001098531.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.001479
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.49
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]
RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-47737684-G-A is Benign according to our data. Variant chr12-47737684-G-A is described in ClinVar as [Benign]. Clinvar id is 715031.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.49 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RAPGEF3NM_001098531.4 linkuse as main transcriptc.2655C>T p.Cys885= splice_region_variant, synonymous_variant 28/28 ENST00000449771.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAPGEF3ENST00000449771.7 linkuse as main transcriptc.2655C>T p.Cys885= splice_region_variant, synonymous_variant 28/282 NM_001098531.4 P4O95398-1
RPAP3-DTENST00000547799.5 linkuse as main transcriptn.451-1231G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000821
AC:
125
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00281
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000955
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000634
AC:
157
AN:
247654
Hom.:
0
AF XY:
0.000598
AC XY:
80
AN XY:
133880
show subpopulations
Gnomad AFR exome
AF:
0.0000623
Gnomad AMR exome
AF:
0.000813
Gnomad ASJ exome
AF:
0.00241
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000958
Gnomad NFE exome
AF:
0.000824
Gnomad OTH exome
AF:
0.00166
GnomAD4 exome
AF:
0.000869
AC:
1269
AN:
1460638
Hom.:
1
Cov.:
30
AF XY:
0.000798
AC XY:
580
AN XY:
726570
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.00105
Gnomad4 ASJ exome
AF:
0.00223
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000132
Gnomad4 NFE exome
AF:
0.000988
Gnomad4 OTH exome
AF:
0.000828
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000821
AC:
125
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.000752
AC XY:
56
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00281
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000956
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000894
Hom.:
0
Bravo
AF:
0.000997
EpiCase
AF:
0.00104
EpiControl
AF:
0.00125

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeAug 13, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.53
Cadd
Benign
13
Dann
Benign
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0015
dbscSNV1_RF
Benign
0.0060
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

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

Other links and lift over

dbSNP: rs146714167; hg19: chr12-48131467; API