10-69572545-C-T

Position:

• chr10-69572545-C-T

Variant summary

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

The ENST00000242462.5(NEUROG3):​c.499G>A​(p.Gly167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,608,162 control chromosomes in the GnomAD database, including 1,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (122 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1550 hom.)
• Consequence: NEUROG3 ENST00000242462.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.66

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=0.0026093423).
• BP6: Variant 10-69572545-C-T is Benign according to our data. Variant chr10-69572545-C-T is described in ClinVar as [Benign]. Clinvar id is 129764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEUROG3	NM_020999.4	c.499G>A	p.Gly167Arg	missense_variant	2/2	ENST00000242462.5	NP_066279.2
NEUROG3	XM_017016280.2	c.499G>A	p.Gly167Arg	missense_variant	2/2		XP_016871769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEUROG3	ENST00000242462.5	c.499G>A	p.Gly167Arg	missense_variant	2/2	1	NM_020999.4	ENSP00000242462	P1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5081 AN: 152148 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.00792

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0476

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0373 AC: 8718 AN: 233760 Hom.: 195 AF XY: 0.0393 AC XY: 5025 AN XY: 127762

Gnomad AFR exome AF: 0.00699

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.0653

Gnomad EAS exome AF: 0.000350

Gnomad SAS exome AF: 0.0402

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0433 AC: 62996 AN: 1455896 Hom.: 1550 Cov.: 37 AF XY: 0.0436 AC XY: 31586 AN XY: 723888

Gnomad4 AFR exome AF: 0.00790

Gnomad4 AMR exome AF: 0.0334

Gnomad4 ASJ exome AF: 0.0667

Gnomad4 EAS exome AF: 0.000382

Gnomad4 SAS exome AF: 0.0417

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0450

GnomAD4 genome AF: 0.0333 AC: 5075 AN: 152266 Hom.: 122 Cov.: 33 AF XY: 0.0323 AC XY: 2404 AN XY: 74460

Gnomad4 AFR AF: 0.00789

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0476

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.0463 Hom.: 57

Bravo AF: 0.0344

TwinsUK AF: 0.0426 AC: 158

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.00716 AC: 31

ESP6500EA AF: 0.0466 AC: 398

ExAC AF: 0.0353 AC: 4259

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
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 -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.072	T
Polyphen		0.15	B
Vest4		0.16
MutPred		0.25		Gain of solvent accessibility (P = 0.0097);
MPC		1.2
ClinPred		0.030	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.60

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: rs41277236; hg19: chr10-71332301;