2-232970265-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 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 NM_019850.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 31 publications found

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]

ENSG00000222001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGEF	NM_019850.3	MANE Select	c.332T>C	p.Met111Thr	missense	Exon 3 of 15	NP_062824.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGEF	ENST00000264051.8	TSL:1 MANE Select	c.332T>C	p.Met111Thr	missense	Exon 3 of 15	ENSP00000264051.3
	NGEF	ENST00000414326.1	TSL:2	c.236T>C	p.Met79Thr	missense	Exon 2 of 2	ENSP00000405053.1
	ENSG00000222001	ENST00000783807.1		n.68-42490A>G		intron	N/A

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

GnomAD2 exomes AF: 0.845 AC: 205120 AN: 242756 AF XY: 0.835

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 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

African (AFR) AF: 0.920 AC: 30198 AN: 32810

American (AMR) AF: 0.910 AC: 38623 AN: 42448

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 18879 AN: 25940

East Asian (EAS) AF: 0.832 AC: 32303 AN: 38824

South Asian (SAS) AF: 0.734 AC: 62204 AN: 84760

European-Finnish (FIN) AF: 0.877 AC: 46786 AN: 53318

Middle Eastern (MID) AF: 0.819 AC: 4674 AN: 5710

European-Non Finnish (NFE) AF: 0.855 AC: 947614 AN: 1108488

Other (OTH) AF: 0.843 AC: 50558 AN: 59974

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

African (AFR) AF: 0.919 AC: 38120 AN: 41494

American (AMR) AF: 0.868 AC: 13277 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2491 AN: 3470

East Asian (EAS) AF: 0.837 AC: 4323 AN: 5164

South Asian (SAS) AF: 0.728 AC: 3510 AN: 4822

European-Finnish (FIN) AF: 0.872 AC: 9232 AN: 10582

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 58029 AN: 67994

Other (OTH) AF: 0.843 AC: 1776 AN: 2108

Alfa AF: 0.849 Hom.: 190228

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 v4.9

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
PhyloP100		-1.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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