9-129635397-T-G

Position:

• chr9-129635397-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014064.4(NTMT1):​c.605T>G​(p.Leu202Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,264 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NTMT1 NM_014064.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTMT1	NM_014064.4	c.605T>G	p.Leu202Arg	missense_variant	4/4	ENST00000372483.9	NP_054783.2
ASB6	NM_017873.4	c.*2393A>C		3_prime_UTR_variant	6/6	ENST00000277458.5	NP_060343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTMT1	ENST00000372483.9	c.605T>G	p.Leu202Arg	missense_variant	4/4	1	NM_014064.4	ENSP00000361561.4
ASB6	ENST00000277458	c.*2393A>C		3_prime_UTR_variant	6/6	1	NM_017873.4	ENSP00000277458.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461264 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726942

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.605T>G (p.L202R) alteration is located in exon 4 (coding exon 3) of the NTMT1 gene. This alteration results from a T to G substitution at nucleotide position 605, causing the leucine (L) at amino acid position 202 to be replaced by an arginine (R). 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	0.34
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T;T;T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;.;D;D;.;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;.;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D;.;.;.;D;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;.;.;.;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		0.97	D;D;.;D;D;.;D
Vest4		0.76
MutPred		0.83		Gain of disorder (P = 0.0289);Gain of disorder (P = 0.0289);.;Gain of disorder (P = 0.0289);Gain of disorder (P = 0.0289);.;Gain of disorder (P = 0.0289);
MVP		0.35
MPC		1.4
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.75

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: chr9-132397676;