chr2-232892987-A-G

Variant names:

• chr2-232892987-A-G
• rs895432
• NM_019850.3:c.1053T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_019850.3(NGEF):​c.1053T>C​(p.Ile351Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,613,308 control chromosomes in the GnomAD database, including 731,888 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.96 (70399 hom., cov: 33)
  • Exomes 𝑓: 0.95 (661489 hom.)
• Consequence: NGEF NM_019850.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.387
• Publications: 17 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.087).
• BP7: Synonymous conserved (PhyloP=0.387 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGEF	NM_019850.3	c.1053T>C	p.Ile351Ile	synonymous_variant	Exon 7 of 15	ENST00000264051.8	NP_062824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGEF	ENST00000264051.8	c.1053T>C	p.Ile351Ile	synonymous_variant	Exon 7 of 15	1	NM_019850.3	ENSP00000264051.3
NGEF	ENST00000373552.8	c.777T>C	p.Ile259Ile	synonymous_variant	Exon 5 of 13	2		ENSP00000362653.4
NGEF	ENST00000416114.3	c.222T>C	p.Ile74Ile	synonymous_variant	Exon 3 of 6	3		ENSP00000401063.1
NGEF	ENST00000420650.2	n.430T>C		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146233 AN: 152206 Hom.: 70341 Cov.: 33

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.956

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.949 AC: 237850 AN: 250664 AF XY: 0.948

Gnomad AFR exome AF: 0.989

Gnomad AMR exome AF: 0.952

Gnomad ASJ exome AF: 0.992

Gnomad EAS exome AF: 0.883

Gnomad FIN exome AF: 0.947

Gnomad NFE exome AF: 0.956

Gnomad OTH exome AF: 0.950

GnomAD4 exome AF: 0.951 AC: 1389963 AN: 1460984 Hom.: 661489 Cov.: 49 AF XY: 0.951 AC XY: 690917 AN XY: 726738

African (AFR) AF: 0.992 AC: 33221 AN: 33480

American (AMR) AF: 0.950 AC: 42460 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25955 AN: 26134

East Asian (EAS) AF: 0.919 AC: 36483 AN: 39688

South Asian (SAS) AF: 0.924 AC: 79701 AN: 86218

European-Finnish (FIN) AF: 0.948 AC: 50114 AN: 52876

Middle Eastern (MID) AF: 0.979 AC: 5641 AN: 5764

European-Non Finnish (NFE) AF: 0.953 AC: 1059190 AN: 1111758

Other (OTH) AF: 0.947 AC: 57198 AN: 60376

GnomAD4 genome AF: 0.961 AC: 146350 AN: 152324 Hom.: 70399 Cov.: 33 AF XY: 0.960 AC XY: 71464 AN XY: 74476

African (AFR) AF: 0.990 AC: 41164 AN: 41570

American (AMR) AF: 0.952 AC: 14568 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3435 AN: 3472

East Asian (EAS) AF: 0.887 AC: 4594 AN: 5180

South Asian (SAS) AF: 0.913 AC: 4407 AN: 4826

European-Finnish (FIN) AF: 0.950 AC: 10085 AN: 10620

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.956 AC: 65015 AN: 68034

Other (OTH) AF: 0.967 AC: 2045 AN: 2114

Alfa AF: 0.960 Hom.: 59965

Bravo AF: 0.964

Asia WGS AF: 0.906 AC: 3154 AN: 3478

EpiCase AF: 0.960

EpiControl AF: 0.959

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs895432; hg19: chr2-233757697; COSMIC: COSV108036650; COSMIC: COSV108036650;