dbSNP rs770935946: NEUROG3:p.Arg191* (chr10-69572473-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

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

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
permanent neonatal diabetes mellitus
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

NEUROG3 links:

ENSG00000236154 (HGNC:):

ENSG00000236154 links:

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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROG3	NM_020999.4	MANE Select	c.571C>T	p.Arg191*	stop_gained	Exon 2 of 2	NP_066279.2	Q9Y4Z2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEUROG3	ENST00000242462.5	TSL:1 MANE Select	c.571C>T	p.Arg191*	stop_gained	Exon 2 of 2	ENSP00000242462.4	Q9Y4Z2
NEUROG3	ENST00000929784.1		c.571C>T	p.Arg191*	stop_gained	Exon 2 of 2	ENSP00000599843.1
ENSG00000236154	ENST00000839697.1		n.363G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000150

AC:

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:

AN:

1437474

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32772

American (AMR)

AF:

0.00

AC:

AN:

41232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25746

East Asian (EAS)

AF:

0.00

AC:

AN:

38192

South Asian (SAS)

AF:

0.00

AC:

AN:

83876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1101038

Other (OTH)

AF:

0.00

AC:

AN:

59344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000168

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.076

PhyloP100

0.33

Vest4

0.68

GERP RS

-1.4

Mutation Taster

=122/78

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over