10-69572467-C-T

Variant names:

• chr10-69572467-C-T
• rs762942188
• NM_020999.4:c.577G>A

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.577G>A​(p.Gly193Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,589,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G193G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: NEUROG3 NM_020999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.625
• Publications: 1 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, 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=0.12126452).

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.577G>A	p.Gly193Arg	missense	Exon 2 of 2	NP_066279.2	Q9Y4Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROG3	ENST00000242462.5	TSL:1 MANE Select	c.577G>A	p.Gly193Arg	missense	Exon 2 of 2	ENSP00000242462.4	Q9Y4Z2
	NEUROG3	ENST00000929784.1		c.577G>A	p.Gly193Arg	missense	Exon 2 of 2	ENSP00000599843.1
	ENSG00000236154	ENST00000839697.1		n.357C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000100 AC: 2 AN: 200068 AF XY: 0.00000908

Gnomad AFR exome AF: 0.0000922

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000110

Gnomad EAS 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: 0.00000626 AC: 9 AN: 1437504 Hom.: 0 Cov.: 37 AF XY: 0.00000420 AC XY: 3 AN XY: 713600

African (AFR) AF: 0.0000305 AC: 1 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 38248

South Asian (SAS) AF: 0.00 AC: 0 AN: 83836

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101298

Other (OTH) AF: 0.00 AC: 0 AN: 59360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.63
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.027	B
Vest4		0.19
MutPred		0.33		Gain of solvent accessibility (P = 0.0097)
MVP		0.89
MPC		0.49
ClinPred		0.11	T
GERP RS		1.0
Varity_R		0.095
gMVP		0.72
Mutation Taster		=92/8	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: rs762942188; hg19: chr10-71332223;