Genetic Variant NGRN:p.Pro45Gln (chr15-90265846-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001033088.3(NGRN):c.134C>A(p.Pro45Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NGRN
NM_001033088.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

NGRN (HGNC:18077): (neugrin, neurite outgrowth associated) Enables rRNA binding activity. Involved in positive regulation of mitochondrial translation. Located in several cellular components, including intercellular bridge; mitotic spindle; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

NGRN links:

ENSG00000261147 (HGNC:):

ENSG00000261147 links:

CIB1 (HGNC:16920): (calcium and integrin binding 1) This gene encodes a member of the EF-hand domain-containing calcium-binding superfamily. The encoded protein interacts with many other proteins, including the platelet integrin alpha-IIb-beta-3, DNA-dependent protein kinase, presenilin-2, focal adhesion kinase, p21 activated kinase, and protein kinase D. The encoded protein may be involved in cell survival and proliferation, and is associated with several disease states including cancer and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2013]

CIB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3120348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGRN	NM_001033088.3 link	c.134C>A	p.Pro45Gln	missense_variant	Exon 1 of 3	ENST00000379095.5	NP_001028260.2	Q9NPE2-2
NGRN	NR_028052.1 link	n.184C>A		non_coding_transcript_exon_variant	Exon 1 of 2
CIB1	NR_102428.1 link	n.-87G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NGRN	ENST00000379095.5 link	c.134C>A	p.Pro45Gln	missense_variant	Exon 1 of 3	1	NM_001033088.3	ENSP00000368389.4	Q9NPE2-2
NGRN	ENST00000331497.3 link	n.188C>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
ENSG00000261147	ENST00000561573.1 link	n.*1789-442C>A		intron_variant	Intron 11 of 12	2		ENSP00000456615.1	H3BSA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722876

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134C>A (p.P45Q) alteration is located in exon 1 (coding exon 1) of the NGRN gene. This alteration results from a C to A substitution at nucleotide position 134, causing the proline (P) at amino acid position 45 to be replaced by a glutamine (Q). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.73

M_CAP

Benign

0.026

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

REVEL

Benign

0.21

Sift

Benign

0.038

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.43

MutPred

0.20

Loss of loop (P = 9e-04);

MVP

0.67

MPC

0.45

ClinPred

0.97

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over