Variant 10-69572463-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020999.4(NEUROG3):c.581T>G(p.Leu194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,752 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 (★). Synonymous variant affecting the same amino acid position (i.e. L194L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NEUROG3
NM_020999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.566

Variant links:

Genes affected

NEUROG3 (HGNC:13806): (neurogenin 3) The protein encoded by this gene is a basic helix-loop-helix (bHLH) transcription factor involved in neurogenesis. The encoded protein likely acts as a heterodimer with another bHLH protein. Defects in this gene are a cause of congenital malabsorptive diarrhea 4 (DIAR4).[provided by RefSeq, May 2010]

NEUROG3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21966991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEUROG3	NM_020999.4 linkuse as main transcript	c.581T>G	p.Leu194Arg	missense_variant	2/2	ENST00000242462.5
NEUROG3	XM_017016280.2 linkuse as main transcript	c.581T>G	p.Leu194Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROG3	ENST00000242462.5 linkuse as main transcript	c.581T>G	p.Leu194Arg	missense_variant	2/2	1	NM_020999.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000496

AC:

AN:

201494

Hom.:

AF XY:

0.00

AC XY:

AN XY:

111038

show subpopulations

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:

0.0000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713828

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:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000842

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 194 of the NEUROG3 protein (p.Leu194Arg). This variant is present in population databases (rs773447910, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with NEUROG3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.20

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

0.86

Vest4

0.22

MutPred

0.40

Gain of solvent accessibility (P = 0.0338);

MVP

0.89

MPC

0.60

ClinPred

0.55

GERP RS

3.7

Varity_R

0.17

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over