9-129635367-G-A

Variant names:

• chr9-129635367-G-A
• NM_014064.4:c.575G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014064.4(NTMT1):​c.575G>A​(p.Arg192Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTMT1 NM_014064.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08475149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTMT1	NM_014064.4	c.575G>A	p.Arg192Lys	missense_variant	Exon 4 of 4	ENST00000372483.9	NP_054783.2
ASB6	NM_017873.4	c.*2423C>T		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.575G>A	p.Arg192Lys	missense_variant	Exon 4 of 4	1	NM_014064.4	ENSP00000361561.4
ASB6	ENST00000277458	c.*2423C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_017873.4	ENSP00000277458.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575G>A (p.R192K) alteration is located in exon 4 (coding exon 3) of the NTMT1 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the arginine (R) at amino acid position 192 to be replaced by a lysine (K). 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	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.024	T;T;T;T;T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	.;.;T;T;.;.;.
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.085	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;N;.;N;N;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.16	N;.;.;.;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.93	T;.;.;.;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;.;B
Vest4		0.068
MutPred		0.45		Gain of catalytic residue at R192 (P = 0.0154);Gain of catalytic residue at R192 (P = 0.0154);.;Gain of catalytic residue at R192 (P = 0.0154);Gain of catalytic residue at R192 (P = 0.0154);.;Gain of catalytic residue at R192 (P = 0.0154);
MVP		0.17
MPC		0.46
ClinPred		0.090	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-132397646;