2-232884012-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_019850.3(NGEF):​c.1570G>A​(p.Asp524Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NGEF
NM_019850.3 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.40
Variant links:
Genes affected
NGEF (HGNC:7807): (neuronal guanine nucleotide exchange factor) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including activation of GTPase activity; ephrin receptor signaling pathway; and negative regulation of dendritic spine morphogenesis. Predicted to be located in cytosol. Predicted to be active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NGEFNM_019850.3 linkc.1570G>A p.Asp524Asn missense_variant Exon 11 of 15 ENST00000264051.8 NP_062824.2 Q8N5V2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NGEFENST00000264051.8 linkc.1570G>A p.Asp524Asn missense_variant Exon 11 of 15 1 NM_019850.3 ENSP00000264051.3 Q8N5V2-1
NGEFENST00000373552.8 linkc.1294G>A p.Asp432Asn missense_variant Exon 9 of 13 2 ENSP00000362653.4 Q8N5V2-3
NGEFENST00000424488.5 linkc.226G>A p.Asp76Asn missense_variant Exon 4 of 6 3 ENSP00000387591.2 H7BZ39
NGEFENST00000489127.1 linkn.390G>A non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459922
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 04, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1570G>A (p.D524N) alteration is located in exon 11 (coding exon 10) of the NGEF gene. This alteration results from a G to A substitution at nucleotide position 1570, causing the aspartic acid (D) at amino acid position 524 to be replaced by an asparagine (N). 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
0.83
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;.;D
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.051
D
MetaRNN
Uncertain
0.51
D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.8
D;D;.
REVEL
Uncertain
0.44
Sift
Benign
0.080
T;T;.
Sift4G
Benign
0.12
T;T;T
Polyphen
0.90
P;.;.
Vest4
0.47
MutPred
0.66
Loss of sheet (P = 0.0126);.;.;
MVP
0.74
MPC
1.1
ClinPred
0.99
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.39
gMVP
0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233748722; API