10-69572485-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020999.4(NEUROG3):c.559T>A(p.Ser187Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000181 in 1,436,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NEUROG3 NM_020999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26212823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEUROG3	NM_020999.4	c.559T>A	p.Ser187Thr	missense_variant	2/2	ENST00000242462.5
NEUROG3	XM_017016280.2	c.559T>A	p.Ser187Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEUROG3	ENST00000242462.5	c.559T>A	p.Ser187Thr	missense_variant	2/2	1	NM_020999.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000507 AC: 1 AN: 197354 Hom.: 0 AF XY: 0.00000921 AC XY: 1 AN XY: 108592

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000181 AC: 26 AN: 1436524 Hom.: 0 Cov.: 37 AF XY: 0.0000210 AC XY: 15 AN XY: 712944

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000218

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The c.559T>A (p.S187T) alteration is located in exon 2 (coding exon 1) of the NEUROG3 gene. This alteration results from a T to A substitution at nucleotide position 559, causing the serine (S) at amino acid position 187 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.26
Sift	Benign	0.075	T
Sift4G	Uncertain	0.039	D
Polyphen		0.47	P
Vest4		0.29
MutPred		0.25		Gain of glycosylation at S187 (P = 0.0477);
MVP		0.98
MPC		1.2
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.74

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: rs1224222918; hg19: chr10-71332241;