10-69572505-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_020999.4(NEUROG3):c.539G>A(p.Gly180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,440,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G180S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: NEUROG3 NM_020999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097927034).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000243 (35/1440986) while in subpopulation SAS AF= 0.000309 (26/84252). AF 95% confidence interval is 0.000216. There are 0 homozygotes in gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEUROG3	NM_020999.4	c.539G>A	p.Gly180Asp	missense_variant	2/2	ENST00000242462.5
NEUROG3	XM_017016280.2	c.539G>A	p.Gly180Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROG3	ENST00000242462.5	c.539G>A	p.Gly180Asp	missense_variant	2/2	1	NM_020999.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000291 AC: 6 AN: 205900 Hom.: 0 AF XY: 0.0000442 AC XY: 5 AN XY: 113078

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: 0.000215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 35 AN: 1440986 Hom.: 0 Cov.: 37 AF XY: 0.0000377 AC XY: 27 AN XY: 715432

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: 0.000309

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000840

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000418 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 180 of the NEUROG3 protein (p.Gly180Asp). This variant is present in population databases (rs764802599, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NEUROG3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.098	T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.096	T
Polyphen		0.015	B
Vest4		0.081
MutPred		0.24		Loss of catalytic residue at A179 (P = 0.0787);
MVP		0.95
MPC		0.57
ClinPred		0.14	T
GERP RS		3.8
Varity_R		0.26
gMVP		0.70

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

Other links and lift over

dbSNP: rs764802599; hg19: chr10-71332261;