2-172736005-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_007023.4(RAPGEF4):​c.22C>T​(p.His8Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,479,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H8R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RAPGEF4
NM_007023.4 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89
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-AS1 (HGNC:28081): (RAPGEF4 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31306705).
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAPGEF4NM_007023.4 linkc.22C>T p.His8Tyr missense_variant Exon 1 of 31 ENST00000397081.8 NP_008954.2 Q8WZA2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAPGEF4ENST00000397081.8 linkc.22C>T p.His8Tyr missense_variant Exon 1 of 31 1 NM_007023.4 ENSP00000380271.3 Q8WZA2-1
RAPGEF4ENST00000409036.5 linkc.22C>T p.His8Tyr missense_variant Exon 1 of 28 5 ENSP00000387104.1 E9PB94
RAPGEF4-AS1ENST00000435328.1 linkn.81+121G>A intron_variant Intron 1 of 3 1
RAPGEF4ENST00000484331.5 linkn.132+600C>T intron_variant Intron 1 of 4 4

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151832
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
10
AN:
1327984
Hom.:
0
Cov.:
29
AF XY:
0.00000916
AC XY:
6
AN XY:
655118
show subpopulations
Gnomad4 AFR exome
AF:
0.0000377
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000136
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000765
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151832
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74178
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 18, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.22C>T (p.H8Y) alteration is located in exon 1 (coding exon 1) of the RAPGEF4 gene. This alteration results from a C to T substitution at nucleotide position 22, causing the histidine (H) at amino acid position 8 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.086
T;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.019
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-0.55
N;N
REVEL
Benign
0.093
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.011
D;D
Polyphen
0.011
B;B
Vest4
0.47
MutPred
0.36
Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);
MVP
0.29
MPC
0.66
ClinPred
0.93
D
GERP RS
4.1
Varity_R
0.33
gMVP
0.69

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: rs922884425; hg19: chr2-173600733; API