NM_001136107.2:c.671T>A

Variant names:

• chr1-170167576-T-A
• rs1023526554
• NM_001136107.2:c.671T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136107.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTMT2	NM_001136107.2	MANE Select	c.671T>A	p.Val224Glu	missense	Exon 4 of 4	NP_001129579.1	Q5VVY1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTMT2	ENST00000439373.3	TSL:1 MANE Select	c.671T>A	p.Val224Glu	missense	Exon 4 of 4	ENSP00000408058.3	Q5VVY1
	NTMT2	ENST00000962802.1		c.623T>A	p.Val208Glu	missense	Exon 4 of 4	ENSP00000632861.1
	NTMT2	ENST00000367764.3	TSL:5	n.*13T>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 31

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: 1 AN: 1399406 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000316 AC: 1 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078974

Other (OTH) AF: 0.00 AC: 0 AN: 58002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000965 AC: 4 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.74
MutPred		0.81		Gain of disorder (P = 0.0289)
MVP		0.20
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.79
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs1023526554; hg19: chr1-170136717;