2-232970265-A-G

Position:

• chr2-232970265-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000264051.8(NGEF):​c.332T>C​(p.Met111Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 1,604,406 control chromosomes in the GnomAD database, including 581,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M111I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.87 (57375 hom., cov: 31)
  • Exomes 𝑓: 0.85 (523810 hom.)
• Consequence: NGEF ENST00000264051.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.539071E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGEF	NM_019850.3	c.332T>C	p.Met111Thr	missense_variant	3/15	ENST00000264051.8	NP_062824.2
NGEF	XM_011510923.4	c.332T>C	p.Met111Thr	missense_variant	3/15		XP_011509225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.332T>C	p.Met111Thr	missense_variant	3/15	1	NM_019850.3	ENSP00000264051
NGEF	ENST00000414326.1	c.239T>C	p.Met80Thr	missense_variant	2/2	2		ENSP00000405053

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131751 AN: 152016 Hom.: 57315 Cov.: 31

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.845

GnomAD3 exomes AF: 0.845 AC: 205120 AN: 242756 Hom.: 87213 AF XY: 0.835 AC XY: 109984 AN XY: 131646

Gnomad AFR exome AF: 0.918

Gnomad AMR exome AF: 0.914

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.842

Gnomad SAS exome AF: 0.729

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.850

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.848 AC: 1231839 AN: 1452272 Hom.: 523810 Cov.: 39 AF XY: 0.844 AC XY: 609711 AN XY: 722650

Gnomad4 AFR exome AF: 0.920

Gnomad4 AMR exome AF: 0.910

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.877

Gnomad4 NFE exome AF: 0.855

Gnomad4 OTH exome AF: 0.843

GnomAD4 genome AF: 0.867 AC: 131868 AN: 152134 Hom.: 57375 Cov.: 31 AF XY: 0.865 AC XY: 64337 AN XY: 74382

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.718

Gnomad4 EAS AF: 0.837

Gnomad4 SAS AF: 0.728

Gnomad4 FIN AF: 0.872

Gnomad4 NFE AF: 0.853

Gnomad4 OTH AF: 0.843

Alfa AF: 0.843 Hom.: 92777

Bravo AF: 0.873

TwinsUK AF: 0.855 AC: 3169

ALSPAC AF: 0.852 AC: 3285

ESP6500AA AF: 0.916 AC: 4038

ESP6500EA AF: 0.846 AC: 7272

ExAC AF: 0.843 AC: 102308

Asia WGS AF: 0.766 AC: 2666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0040
DANN	Benign	0.14
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.0094
ClinPred		0.0037	T
GERP RS		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.15

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

Other links and lift over

dbSNP: rs4973588; hg19: chr2-233834975; COSMIC: COSV50914443;