2-232891481-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_019850.3(NGEF):c.1149G>A(p.Glu383=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,612,726 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (7 hom.)
• Consequence: NGEF NM_019850.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-232891481-C-T is Benign according to our data. Variant chr2-232891481-C-T is described in ClinVar as [Benign]. Clinvar id is 770514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00613 (934/152360) while in subpopulation AFR AF= 0.0212 (883/41582). AF 95% confidence interval is 0.0201. There are 13 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NGEF	NM_019850.3	c.1149G>A	p.Glu383=	synonymous_variant	8/15	ENST00000264051.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NGEF	ENST00000264051.8	c.1149G>A	p.Glu383=	synonymous_variant	8/15	1	NM_019850.3
NGEF	ENST00000373552.8	c.873G>A	p.Glu291=	synonymous_variant	6/13	2		P1
NGEF	ENST00000416114.3	c.318G>A	p.Glu106=	synonymous_variant	4/6	3

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 933 AN: 152242 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00152 AC: 380 AN: 249372 Hom.: 6 AF XY: 0.00109 AC XY: 148 AN XY: 135202

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.000724

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: 0.0000357

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000594 AC: 867 AN: 1460366 Hom.: 7 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 726458

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152360 Hom.: 13 Cov.: 33 AF XY: 0.00597 AC XY: 445 AN XY: 74510

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00291 Hom.: 5

Bravo AF: 0.00669

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	12
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61750834; hg19: chr2-233756191; COSMIC: COSV50919330; COSMIC: COSV50919330;