9-129635445-A-G

Variant names:

• chr9-129635445-A-G
• rs748725251
• NM_014064.4:c.653A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014064.4(NTMT1):​c.653A>G​(p.Tyr218Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NTMT1 NM_014064.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

Genes affected

NTMT1 (HGNC:23373): (N-terminal Xaa-Pro-Lys N-methyltransferase 1) The METTL11A gene encodes an N-terminal methyltransferase for the RAN (MIM 601179) guanine nucleotide exchange factor regulator of chromosome condensation 1 (RCC1; MIM 179710). METTL11A enzyme alpha-N-methylates other protein targets such as SET (MIM 600960) and RB (MIM 180200).[supplied by OMIM, Nov 2010]

ASB6 (HGNC:17181): (ankyrin repeat and SOCS box containing 6) The protein encoded by this gene belongs to a family of ankyrin repeat proteins that, along with four other protein families, contain a C-terminal SOCS box motif. Growing evidence suggests that the SOCS box, similar to the F-box, acts as a bridge between specific substrate-binding domains and the more generic proteins that comprise a large family of E3 ubiquitin protein ligases. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTMT1	NM_014064.4	c.653A>G	p.Tyr218Cys	missense_variant	Exon 4 of 4	ENST00000372483.9	NP_054783.2
ASB6	NM_017873.4	c.*2345T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000277458.5	NP_060343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTMT1	ENST00000372483.9	c.653A>G	p.Tyr218Cys	missense_variant	Exon 4 of 4	1	NM_014064.4	ENSP00000361561.4
ASB6	ENST00000277458	c.*2345T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_017873.4	ENSP00000277458.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247960 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460490 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.653A>G (p.Y218C) alteration is located in exon 4 (coding exon 3) of the NTMT1 gene. This alteration results from a A to G substitution at nucleotide position 653, causing the tyrosine (Y) at amino acid position 218 to be replaced by a cysteine (C). 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	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T;T;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	.;.;D;D;.;.;.
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D;.;.;.;D;.;D
REVEL	Benign	0.26
Sift	Benign	0.051	T;.;.;.;T;.;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;D;D;.;D
Vest4		0.69
MutPred		0.67		Loss of catalytic residue at Y218 (P = 0.0508);Loss of catalytic residue at Y218 (P = 0.0508);.;Loss of catalytic residue at Y218 (P = 0.0508);Loss of catalytic residue at Y218 (P = 0.0508);.;Loss of catalytic residue at Y218 (P = 0.0508);
MVP		0.38
MPC		1.5
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.86

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

Other links and lift over

dbSNP: rs748725251; hg19: chr9-132397724;