Genetic Variant RAPGEF4:c.297+2268G>A (chr2-172799881-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007023.4(RAPGEF4):c.297+2268G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,008 control chromosomes in the GnomAD database, including 7,609 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7609 hom., cov: 32)

Consequence

RAPGEF4
NM_007023.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

3 publications found

Variant links:

Genes affected

RAPGEF4 (HGNC:16626): (Rap guanine nucleotide exchange factor 4) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neurotransmitter receptor localization to postsynaptic specialization membrane and regulation of postsynapse organization. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Predicted to be located in plasma membrane. Predicted to be active in glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF4 Gene-Disease associations (from GenCC):

prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RAPGEF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF4	NM_007023.4 link	c.297+2268G>A		intron_variant	Intron 3 of 30	ENST00000397081.8	NP_008954.2	Q8WZA2-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEF4	ENST00000397081.8 link	c.297+2268G>A	intron_variant	Intron 3 of 30	1	NM_007023.4	ENSP00000380271.3	Q8WZA2-1
RAPGEF4	ENST00000409036.5 link	c.297+2268G>A	intron_variant	Intron 3 of 27	5		ENSP00000387104.1	E9PB94
RAPGEF4	ENST00000464976.1 link	n.518+2268G>A	intron_variant	Intron 3 of 3	1
RAPGEF4	ENST00000484331.5 link	n.364+2268G>A	intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47512

AN:

151890

Hom.:

7600

Cov.:

show subpopulations

Gnomad AFR

AF:

0.318

Gnomad AMI

AF:

0.373

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.313

AC:

47547

AN:

152008

Hom.:

7609

Cov.:

AF XY:

0.317

AC XY:

23536

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.318

AC:

13192

AN:

41456

American (AMR)

AF:

0.344

AC:

5250

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

859

AN:

3470

East Asian (EAS)

AF:

0.467

AC:

2415

AN:

5168

South Asian (SAS)

AF:

0.366

AC:

1760

AN:

4806

European-Finnish (FIN)

AF:

0.332

AC:

3501

AN:

10556

Middle Eastern (MID)

AF:

0.264

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.287

AC:

19513

AN:

67974

Other (OTH)

AF:

0.304

AC:

640

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1646

3292

4939

6585

8231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.294

Hom.:

22531

Bravo

AF:

0.313

Asia WGS

AF:

0.397

AC:

1381

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.44

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over