10-69572448-A-G

Position:

• chr10-69572448-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020999.4(NEUROG3):​c.596T>C​(p.Phe199Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,586,694 control chromosomes in the GnomAD database, including 319,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24507 hom., cov: 33)
  • Exomes 𝑓: 0.63 (294737 hom.)
• Consequence: NEUROG3 NM_020999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.90

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0075619E-5).
• BP6: Variant 10-69572448-A-G is Benign according to our data. Variant chr10-69572448-A-G is described in ClinVar as [Benign]. Clinvar id is 129765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEUROG3	NM_020999.4	c.596T>C	p.Phe199Ser	missense_variant	2/2	ENST00000242462.5	NP_066279.2
NEUROG3	XM_017016280.2	c.596T>C	p.Phe199Ser	missense_variant	2/2		XP_016871769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEUROG3	ENST00000242462.5	c.596T>C	p.Phe199Ser	missense_variant	2/2	1	NM_020999.4	ENSP00000242462.4

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83069 AN: 151906 Hom.: 24504 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.544

GnomAD3 exomes AF: 0.561 AC: 113541 AN: 202444 Hom.: 33227 AF XY: 0.561 AC XY: 62600 AN XY: 111680

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.450

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.633 AC: 908369 AN: 1434668 Hom.: 294737 Cov.: 63 AF XY: 0.628 AC XY: 447487 AN XY: 712452

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.555

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.458

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.597

GnomAD4 genome AF: 0.547 AC: 83090 AN: 152026 Hom.: 24507 Cov.: 33 AF XY: 0.544 AC XY: 40395 AN XY: 74300

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.614

Gnomad4 ASJ AF: 0.559

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.442

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.672

Gnomad4 OTH AF: 0.539

Alfa AF: 0.630 Hom.: 59456

Bravo AF: 0.531

TwinsUK AF: 0.672 AC: 2493

ALSPAC AF: 0.671 AC: 2585

ESP6500AA AF: 0.395 AC: 1453

ESP6500EA AF: 0.679 AC: 5305

ExAC AF: 0.534 AC: 62528

Asia WGS AF: 0.404 AC: 1408 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 11206403, 17146417) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital malabsorptive diarrhea 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.72
ClinPred		0.0014	T
GERP RS		2.9
Varity_R		0.052
gMVP		0.48

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: rs4536103; hg19: chr10-71332204; COSMIC: COSV54342350; COSMIC: COSV54342350;