chr10-69572473-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_020999.4(NEUROG3):​c.571C>T​(p.Arg191*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 1,437,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R191R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

NEUROG3
NM_020999.4 stop_gained

Scores

2
1
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.329

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • congenital malabsorptive diarrhea 4
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • permanent neonatal diabetes mellitus
    Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.115 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEUROG3NM_020999.4 linkc.571C>T p.Arg191* stop_gained Exon 2 of 2 ENST00000242462.5 NP_066279.2 Q9Y4Z2
NEUROG3XM_017016280.2 linkc.571C>T p.Arg191* stop_gained Exon 2 of 2 XP_016871769.1 Q9Y4Z2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEUROG3ENST00000242462.5 linkc.571C>T p.Arg191* stop_gained Exon 2 of 2 1 NM_020999.4 ENSP00000242462.4 Q9Y4Z2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.0000150
AC:
3
AN:
199352
AF XY:
0.0000273
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000356
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000904
AC:
13
AN:
1437474
Hom.:
0
Cov.:
37
AF XY:
0.00000841
AC XY:
6
AN XY:
713526
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32772
American (AMR)
AF:
0.00
AC:
0
AN:
41232
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25746
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83876
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49698
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5576
European-Non Finnish (NFE)
AF:
0.0000118
AC:
13
AN:
1101038
Other (OTH)
AF:
0.00
AC:
0
AN:
59344
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.540
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000168
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg191*) in the NEUROG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the NEUROG3 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NEUROG3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2192202). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
30
DANN
Uncertain
0.98
Eigen
Benign
-0.068
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.076
N
PhyloP100
0.33
Vest4
0.68
GERP RS
-1.4
Mutation Taster
=122/78
polymorphism

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

Other links and lift over

dbSNP: rs770935946; hg19: chr10-71332229; COSMIC: COSV54343579; COSMIC: COSV54343579; API