Variant 2-172988220-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007023.4(RAPGEF4):c.1175C>T(p.Thr392Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000448 in 1,609,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

RAPGEF4
NM_007023.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF4	NM_007023.4 linkuse as main transcript	c.1175C>T	p.Thr392Ile	missense_variant	13/31	ENST00000397081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF4	ENST00000397081.8 linkuse as main transcript	c.1175C>T	p.Thr392Ile	missense_variant	13/31	1	NM_007023.4	P1	Q8WZA2-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000216

AC:

AN:

245412

Hom.:

AF XY:

0.000233

AC XY:

AN XY:

133194

show subpopulations

Gnomad AFR exome

AF:

0.000390

Gnomad AMR exome

AF:

0.000210

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000470

AC:

685

AN:

1457702

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

328

AN XY:

725128

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000582

Gnomad4 OTH exome

AF:

0.000399

GnomAD4 genome

AF:

0.000237

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000333

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000549

AC:

ESP6500EA

AF:

0.000490

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000495

EpiControl

AF:

0.000299

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.1175C>T (p.T392I) alteration is located in exon 13 (coding exon 13) of the RAPGEF4 gene. This alteration results from a C to T substitution at nucleotide position 1175, causing the threonine (T) at amino acid position 392 to be replaced by an isoleucine (I). 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

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.29

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.61

D;D;D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.6

L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D

REVEL

Pathogenic

0.74

Sift

Benign

0.064

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.62

P;.;P;.;.;.

Vest4

0.91

MVP

0.87

MPC

1.1

ClinPred

0.057

GERP RS

5.5

Varity_R

0.39

gMVP

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over