rs121917837

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000242462.5(NEUROG3):​c.319C>A​(p.Arg107Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,614,036 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NEUROG3
ENST00000242462.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.43
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a domain bHLH (size 52) in uniprot entity NGN3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000242462.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 10-69572725-G-T is Pathogenic according to our data. Variant chr10-69572725-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEUROG3NM_020999.4 linkuse as main transcriptc.319C>A p.Arg107Ser missense_variant 2/2 ENST00000242462.5 NP_066279.2
NEUROG3XM_017016280.2 linkuse as main transcriptc.319C>A p.Arg107Ser missense_variant 2/2 XP_016871769.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEUROG3ENST00000242462.5 linkuse as main transcriptc.319C>A p.Arg107Ser missense_variant 2/21 NM_020999.4 ENSP00000242462 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152268
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251248
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461768
Hom.:
0
Cov.:
36
AF XY:
0.00000825
AC XY:
6
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000112
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:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000688
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital malabsorptive diarrhea 4 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 20, 2006- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityApr 26, 2018- -
NEUROG3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 29, 2022The NEUROG3 c.319C>A variant is predicted to result in the amino acid substitution p.Arg107Ser. This variant was reported in the homozygous state in multiple individuals with congenital malabsorptive diarrhea (Wang et al. 2006. PubMed ID: 16855267; Rubio-Cabezas et al. 2016. PubMed ID: 27533310; Germán-Díaz et al. 2017. PubMed ID: 28724572). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-71332481-G-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.93
Gain of glycosylation at R107 (P = 0.0465);
MVP
1.0
MPC
1.3
ClinPred
0.99
D
GERP RS
4.5
Varity_R
0.94
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs121917837; hg19: chr10-71332481; API