rs1026231001

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGEF	NM_019850.3	MANE Select	c.1497G>A	p.Met499Ile	missense	Exon 11 of 15	NP_062824.2	Q8N5V2-1
	NGEF	NM_001114090.2		c.1221G>A	p.Met407Ile	missense	Exon 9 of 13	NP_001107562.1	Q8N5V2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGEF	ENST00000264051.8	TSL:1 MANE Select	c.1497G>A	p.Met499Ile	missense	Exon 11 of 15	ENSP00000264051.3	Q8N5V2-1
	NGEF	ENST00000905022.1		c.1596G>A	p.Met532Ile	missense	Exon 12 of 16	ENSP00000575081.1
	NGEF	ENST00000965357.1		c.1596G>A	p.Met532Ile	missense	Exon 12 of 16	ENSP00000635416.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111566

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000544 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.66	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D
Sift4G	Benign	0.067	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
Mutation Taster		=42/58	disease causing

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: rs1026231001; hg19: chr2-233748795;