Variant chr2-232879512-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019850.3(NGEF):c.2110C>A(p.Leu704Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,449,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

NGEF
NM_019850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

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]

NGEF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08789268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGEF	NM_019850.3 linkuse as main transcript	c.2110C>A	p.Leu704Met	missense_variant	15/15	ENST00000264051.8	NP_062824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8 linkuse as main transcript	c.2110C>A	p.Leu704Met	missense_variant	15/15	1	NM_019850.3	ENSP00000264051		Q8N5V2-1
NGEF	ENST00000373552.8 linkuse as main transcript	c.1834C>A	p.Leu612Met	missense_variant	13/13	2		ENSP00000362653	P1	Q8N5V2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251026

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1449574

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

720330

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:

0.0000263

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jul 25, 2023

The c.2110C>A (p.L704M) alteration is located in exon 15 (coding exon 14) of the NGEF gene. This alteration results from a C to A substitution at nucleotide position 2110, causing the leucine (L) at amino acid position 704 to be replaced by a methionine (M). 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

0.090

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.043

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.088

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.20

N;.

MutationTaster

Benign

0.80

N;N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.072

Sift

Benign

0.21

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.31

B;.

Vest4

0.19

MutPred

0.19

Loss of methylation at K703 (P = 0.0362);.;

MVP

0.54

MPC

0.78

ClinPred

0.19

GERP RS

3.4

Varity_R

0.091

gMVP

0.44

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