Genetic Variant NIT2:p.Thr2Ala (chr3-100334795-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_020202.5(NIT2):c.4A>G(p.Thr2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,304,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

NIT2
NM_020202.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.963

Variant links:

Genes affected

NIT2 (HGNC:29878): (nitrilase family member 2) Enables omega-amidase activity. Involved in asparagine metabolic process; glutamine metabolic process; and oxaloacetate metabolic process. Located in centrosome and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

NIT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06568873).

BP6

Variant 3-100334795-A-G is Benign according to our data. Variant chr3-100334795-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2308276.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIT2	NM_020202.5 link	c.4A>G	p.Thr2Ala	missense_variant	Exon 1 of 10	ENST00000394140.9	NP_064587.1	Q9NQR4V9HW91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIT2	ENST00000394140.9 link	c.4A>G	p.Thr2Ala	missense_variant	Exon 1 of 10	1	NM_020202.5	ENSP00000377696.3		Q9NQR4

Frequencies

GnomAD3 genomes

AF:

0.000165

AC:

AN:

151668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.000339

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000278

AC:

AN:

104264

Hom.:

AF XY:

0.000291

AC XY:

AN XY:

58352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000273

AC:

315

AN:

1153178

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

147

AN XY:

552152

show subpopulations

Gnomad4 AFR exome

AF:

0.0000404

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000318

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000165

AC:

AN:

151668

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

74036

show subpopulations

Gnomad4 AFR

AF:

0.0000485

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000339

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000257

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 09, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Benign

0.099

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.23

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.91

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.57

REVEL

Benign

0.19

Sift

Benign

0.58

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.16

MVP

0.35

MPC

0.15

ClinPred

0.058

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over