rs544040415

Variant names:

• chr2-232879665-C-G
• rs544040415
• NM_019850.3:c.1957G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-232879665-C-G
• chr2-232879665-C-T

Variant summary

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

The NM_019850.3(NGEF):​c.1957G>C​(p.Glu653Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E653K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NGEF NM_019850.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69

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.1957G>C	p.Glu653Gln	missense_variant	Exon 15 of 15	ENST00000264051.8	NP_062824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.1957G>C	p.Glu653Gln	missense_variant	Exon 15 of 15	1	NM_019850.3	ENSP00000264051.3
NGEF	ENST00000373552.8	c.1681G>C	p.Glu561Gln	missense_variant	Exon 13 of 13	2		ENSP00000362653.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250756 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726204

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

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.22
Sift	Benign	0.034	D;D
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.47		Loss of catalytic residue at E653 (P = 0.0365);.;
MVP		0.59
MPC		1.7
ClinPred		0.85	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.79

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: rs544040415; hg19: chr2-233744375;