1-170167488-C-G

Variant names:

• chr1-170167488-C-G
• NM_001136107.2:c.583C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001136107.2(NTMT2):​c.583C>G​(p.His195Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,394,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NTMT2 NM_001136107.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.388

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity NTM1B_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTMT2	NM_001136107.2	c.583C>G	p.His195Asp	missense_variant, splice_region_variant	Exon 4 of 4	ENST00000439373.3	NP_001129579.1
NTMT2	XM_011509232.3	c.388C>G	p.His130Asp	missense_variant, splice_region_variant	Exon 5 of 5		XP_011507534.1
NTMT2	XM_011509233.3	c.388C>G	p.His130Asp	missense_variant, splice_region_variant	Exon 6 of 6		XP_011507535.1
NTMT2	XM_011509234.3	c.388C>G	p.His130Asp	missense_variant, splice_region_variant	Exon 5 of 5		XP_011507536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTMT2	ENST00000439373.3	c.583C>G	p.His195Asp	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_001136107.2	ENSP00000408058.3
NTMT2	ENST00000367764.3	n.641C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1394036 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 687100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000385

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583C>G (p.H195D) alteration is located in exon 4 (coding exon 4) of the METTL11B gene. This alteration results from a C to G substitution at nucleotide position 583, causing the histidine (H) at amino acid position 195 to be replaced by an aspartic acid (D). 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	0.63
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.018	D
Polyphen		0.11	B
Vest4		0.43
MutPred		0.85		Gain of ubiquitination at K199 (P = 0.0767);
MVP		0.030
ClinPred		0.99	D
GERP RS		-3.5
Varity_R		0.93
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-170136629;