2-232884085-C-T

Variant names:

• chr2-232884085-C-T
• rs1026231001
• NM_019850.3:c.1497G>A

Variant summary

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

The NM_019850.3(NGEF):​c.1497G>A​(p.Met499Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,876 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: 6.8e-7 (0 hom.)
• Consequence: NGEF NM_019850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 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
NGEF	NM_019850.3	c.1497G>A	p.Met499Ile	missense_variant	Exon 11 of 15	ENST00000264051.8	NP_062824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.1497G>A	p.Met499Ile	missense_variant	Exon 11 of 15	1	NM_019850.3	ENSP00000264051.3
NGEF	ENST00000373552.8	c.1221G>A	p.Met407Ile	missense_variant	Exon 9 of 13	2		ENSP00000362653.4
NGEF	ENST00000424488.5	c.153G>A	p.Met51Ile	missense_variant	Exon 4 of 6	3		ENSP00000387591.2
NGEF	ENST00000489127.1	n.317G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726132

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000544 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1497G>A (p.M499I) 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 1497, causing the methionine (M) at amino acid position 499 to be replaced by an isoleucine (I). 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	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.66	N;N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D;D;.
Sift4G	Benign	0.067	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.70
MutPred		0.48		Gain of catalytic residue at M499 (P = 0.0262);.;.;
MVP		0.84
MPC		1.4
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.37

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: rs1026231001; hg19: chr2-233748795;