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GeneBe

2-173001330-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_007023.4(RAPGEF4):c.1644G>A(p.Pro548=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,864 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0069 ( 15 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 14 hom. )

Consequence

RAPGEF4
NM_007023.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.283
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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=-0.32).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-173001330-G-A is Benign according to our data. Variant chr2-173001330-G-A is described in ClinVar as [Benign]. Clinvar id is 774835.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=0.283 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00687 (1046/152148) while in subpopulation AFR AF= 0.0221 (919/41504). AF 95% confidence interval is 0.021. There are 15 homozygotes in gnomad4. There are 501 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1037 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RAPGEF4NM_007023.4 linkuse as main transcriptc.1644G>A p.Pro548= synonymous_variant 17/31 ENST00000397081.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAPGEF4ENST00000397081.8 linkuse as main transcriptc.1644G>A p.Pro548= synonymous_variant 17/311 NM_007023.4 P1Q8WZA2-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00682
AC:
1037
AN:
152030
Hom.:
14
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0220
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00295
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00520
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000588
Gnomad OTH
AF:
0.00479
GnomAD3 exomes
AF:
0.00247
AC:
616
AN:
249444
Hom.:
7
AF XY:
0.00238
AC XY:
322
AN XY:
135342
show subpopulations
Gnomad AFR exome
AF:
0.0224
Gnomad AMR exome
AF:
0.00148
Gnomad ASJ exome
AF:
0.00139
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00389
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000645
Gnomad OTH exome
AF:
0.00182
GnomAD4 exome
AF:
0.00125
AC:
1834
AN:
1461716
Hom.:
14
Cov.:
32
AF XY:
0.00130
AC XY:
942
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.0224
Gnomad4 AMR exome
AF:
0.00132
Gnomad4 ASJ exome
AF:
0.00119
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00397
Gnomad4 FIN exome
AF:
0.000243
Gnomad4 NFE exome
AF:
0.000451
Gnomad4 OTH exome
AF:
0.00194
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00687
AC:
1046
AN:
152148
Hom.:
15
Cov.:
32
AF XY:
0.00674
AC XY:
501
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0221
Gnomad4 AMR
AF:
0.00294
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00562
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000588
Gnomad4 OTH
AF:
0.00474
Alfa
AF:
0.00212
Hom.:
3
Bravo
AF:
0.00734
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.000600
EpiControl
AF:
0.00107

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 testingInvitaeJun 06, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
Cadd
Benign
12
Dann
Benign
0.68

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

LitVar

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

Other links and lift over

dbSNP: rs35825006; hg19: chr2-173866058; API