NM_020999.4:c.596T>C

Variant names:

• chr10-69572448-A-G
• rs4536103
• NM_020999.4:c.596T>C

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.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. 16/21 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
• Publications: 41 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=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 VariationId 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.

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.596T>C	p.Phe199Ser	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.596T>C	p.Phe199Ser	missense	Exon 2 of 2	ENSP00000242462.4
	ENSG00000236154	ENST00000839697.1		n.338A>G		non_coding_transcript_exon	Exon 1 of 4
	ENSG00000236154	ENST00000839692.1		n.161+1775A>G		intron	N/A

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

GnomAD2 exomes AF: 0.561 AC: 113541 AN: 202444 AF XY: 0.561

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 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

African (AFR) AF: 0.309 AC: 10143 AN: 32810

American (AMR) AF: 0.581 AC: 24147 AN: 41532

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 14310 AN: 25772

East Asian (EAS) AF: 0.302 AC: 11599 AN: 38408

South Asian (SAS) AF: 0.458 AC: 38439 AN: 83904

European-Finnish (FIN) AF: 0.646 AC: 29807 AN: 46114

Middle Eastern (MID) AF: 0.488 AC: 2757 AN: 5652

European-Non Finnish (NFE) AF: 0.674 AC: 741713 AN: 1101106

Other (OTH) AF: 0.597 AC: 35454 AN: 59370

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

African (AFR) AF: 0.332 AC: 13788 AN: 41490

American (AMR) AF: 0.614 AC: 9401 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1938 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1657 AN: 5110

South Asian (SAS) AF: 0.442 AC: 2127 AN: 4814

European-Finnish (FIN) AF: 0.641 AC: 6780 AN: 10574

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.672 AC: 45644 AN: 67956

Other (OTH) AF: 0.539 AC: 1137 AN: 2110

Alfa AF: 0.625 Hom.: 78493

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Congenital malabsorptive diarrhea 4 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.9
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
Mutation Taster		=95/5	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: rs4536103; hg19: chr10-71332204; COSMIC: COSV54342350; COSMIC: COSV54342350;