NM_020999.4:c.605G>T

Variant names:

• chr10-69572439-C-A
• rs1318653780
• NM_020999.4:c.605G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020999.4(NEUROG3):​c.605G>T​(p.Cys202Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,437,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: NEUROG3 NM_020999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.137
• Publications: 0 publications found

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

ENSG00000236154 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14947668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROG3	NM_020999.4	c.605G>T	p.Cys202Phe	missense_variant	Exon 2 of 2	ENST00000242462.5	NP_066279.2
NEUROG3	XM_017016280.2	c.605G>T	p.Cys202Phe	missense_variant	Exon 2 of 2		XP_016871769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROG3	ENST00000242462.5	c.605G>T	p.Cys202Phe	missense_variant	Exon 2 of 2	1	NM_020999.4	ENSP00000242462.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000492 AC: 1 AN: 203290 AF XY: 0.00

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: 0.0000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000202 AC: 29 AN: 1437196 Hom.: 0 Cov.: 29 AF XY: 0.0000182 AC XY: 13 AN XY: 713964

African (AFR) AF: 0.00 AC: 0 AN: 32882

American (AMR) AF: 0.00 AC: 0 AN: 42372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.00 AC: 0 AN: 84134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.0000263 AC: 29 AN: 1103190

Other (OTH) AF: 0.00 AC: 0 AN: 59568

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 202 of the NEUROG3 protein (p.Cys202Phe). 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. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NEUROG3-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.14
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.090	T
Polyphen		0.31	B
Vest4		0.13
MutPred		0.25		Gain of solvent accessibility (P = 0.0216);
MVP		0.88
MPC		0.68
ClinPred		0.21	T
GERP RS		0.51
Varity_R		0.49
gMVP		0.63
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs1318653780; hg19: chr10-71332195;