rs41277236

Variant names:

• chr10-69572545-C-T
• rs41277236
• NM_020999.4:c.499G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020999.4(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. 13/21 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 NM_020999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.66
• Publications: 23 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: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROG3	NM_020999.4	MANE Select	c.499G>A	p.Gly167Arg	missense	Exon 2 of 2	NP_066279.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEUROG3	ENST00000242462.5	TSL:1 MANE Select	c.499G>A	p.Gly167Arg	missense	Exon 2 of 2	ENSP00000242462.4
	ENSG00000236154	ENST00000839697.1		n.435C>T		non_coding_transcript_exon	Exon 1 of 4
	ENSG00000236154	ENST00000839692.1		n.161+1872C>T		intron	N/A

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

GnomAD2 exomes AF: 0.0373 AC: 8718 AN: 233760 AF XY: 0.0393

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 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

African (AFR) AF: 0.00790 AC: 263 AN: 33288

American (AMR) AF: 0.0334 AC: 1467 AN: 43914

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 1736 AN: 26010

East Asian (EAS) AF: 0.000382 AC: 15 AN: 39242

South Asian (SAS) AF: 0.0417 AC: 3576 AN: 85666

European-Finnish (FIN) AF: 0.0265 AC: 1398 AN: 52844

Middle Eastern (MID) AF: 0.0804 AC: 447 AN: 5560

European-Non Finnish (NFE) AF: 0.0463 AC: 51388 AN: 1109280

Other (OTH) AF: 0.0450 AC: 2706 AN: 60092

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

African (AFR) AF: 0.00789 AC: 328 AN: 41560

American (AMR) AF: 0.0482 AC: 738 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.0381 AC: 184 AN: 4826

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10626

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0476 AC: 3238 AN: 67994

Other (OTH) AF: 0.0507 AC: 107 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.7
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
Mutation Taster		=96/4	polymorphism (auto)

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: rs41277236; hg19: chr10-71332301;