2-232970265-A-G

Variant names:

• chr2-232970265-A-G
• rs4973588
• NM_019850.3:c.332T>C

Variant summary

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

The NM_019850.3(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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.87 (57375 hom., cov: 31)
  • Exomes 𝑓: 0.85 (523810 hom.)
• Consequence: NGEF NM_019850.3 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 rank	MANE	Protein	UniProt
NGEF	NM_019850.3	c.332T>C	p.Met111Thr	missense_variant	Exon 3 of 15	ENST00000264051.8	NP_062824.2
NGEF	XM_011510923.4	c.332T>C	p.Met111Thr	missense_variant	Exon 3 of 15		XP_011509225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.332T>C	p.Met111Thr	missense_variant	Exon 3 of 15	1	NM_019850.3	ENSP00000264051.3
NGEF	ENST00000414326.1	c.236T>C	p.Met79Thr	missense_variant	Exon 2 of 2	2		ENSP00000405053.1

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
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;