Genetic Variant NTMT2:p.Ile91Thr (chr1-170160635-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001136107.2(NTMT2):c.272T>C(p.Ile91Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,551,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NTMT2
NM_001136107.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052268803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTMT2	NM_001136107.2 link	c.272T>C	p.Ile91Thr	missense_variant	Exon 2 of 4	ENST00000439373.3	NP_001129579.1	Q5VVY1
NTMT2	XM_011509232.3 link	c.77T>C	p.Ile26Thr	missense_variant	Exon 3 of 5		XP_011507534.1
NTMT2	XM_011509233.3 link	c.77T>C	p.Ile26Thr	missense_variant	Exon 4 of 6		XP_011507535.1
NTMT2	XM_011509234.3 link	c.77T>C	p.Ile26Thr	missense_variant	Exon 3 of 5		XP_011507536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTMT2	ENST00000439373.3 link	c.272T>C	p.Ile91Thr	missense_variant	Exon 2 of 4	1	NM_001136107.2	ENSP00000408058.3		Q5VVY1
NTMT2	ENST00000367764.3 link	n.267T>C		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

156484

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

82824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000816

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000594

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1399038

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

690000

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.0000843

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.000113

ExAC

AF:

0.0000400

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272T>C (p.I91T) alteration is located in exon 2 (coding exon 2) of the METTL11B gene. This alteration results from a T to C substitution at nucleotide position 272, causing the isoleucine (I) at amino acid position 91 to be replaced by a threonine (T). 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

Benign

0.065

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.0030

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.0074

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.13

PrimateAI

Benign

0.44

PROVEAN

Benign

1.6

REVEL

Benign

0.050

Sift

Benign

0.33

Sift4G

Benign

0.58

Polyphen

0.27

Vest4

0.21

MutPred

0.38

Gain of disorder (P = 0.0167);

MVP

0.030

ClinPred

0.15

GERP RS

4.6

Varity_R

0.36

gMVP

0.50

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

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