Genetic Variant NTMT2:p.Val224Glu (chr1-170167576-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136107.2(NTMT2):c.671T>A(p.Val224Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000322 in 1,551,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NTMT2
NM_001136107.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

Variant links:

Genes affected

NTMT2 (HGNC:31932): (N-terminal Xaa-Pro-Lys N-methyltransferase 2) Enables N-terminal protein N-methyltransferase activity. Involved in N-terminal protein amino acid methylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NTMT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTMT2	NM_001136107.2 link	c.671T>A	p.Val224Glu	missense_variant	Exon 4 of 4	ENST00000439373.3	NP_001129579.1	Q5VVY1
NTMT2	XM_011509232.3 link	c.476T>A	p.Val159Glu	missense_variant	Exon 5 of 5		XP_011507534.1
NTMT2	XM_011509233.3 link	c.476T>A	p.Val159Glu	missense_variant	Exon 6 of 6		XP_011507535.1
NTMT2	XM_011509234.3 link	c.476T>A	p.Val159Glu	missense_variant	Exon 5 of 5		XP_011507536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTMT2	ENST00000439373.3 link	c.671T>A	p.Val224Glu	missense_variant	Exon 4 of 4	1	NM_001136107.2	ENSP00000408058.3		Q5VVY1
NTMT2	ENST00000367764.3 link	n.*13T>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399406

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671T>A (p.V224E) alteration is located in exon 4 (coding exon 4) of the METTL11B gene. This alteration results from a T to A substitution at nucleotide position 671, causing the valine (V) at amino acid position 224 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.74

MutPred

0.81

Gain of disorder (P = 0.0289);

MVP

0.20

ClinPred

0.99

GERP RS

4.0

Varity_R

0.98

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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