21-28882986-T-C

Position:

• chr21-28882986-T-C

Variant summary

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

The NM_013240.6(N6AMT1):​c.220A>G​(p.Met74Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,429,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: N6AMT1 NM_013240.6 missense, splice_region
• Scores: Splicing: ADA: 0.07572
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.463

Genes affected

N6AMT1 (HGNC:16021): (N-6 adenine-specific DNA methyltransferase 1) This gene encodes an N(6)-adenine-specific DNA methyltransferase. The encoded enzyme may be involved in the methylation of release factor I during translation termination. This enzyme is also involved in converting the arsenic metabolite monomethylarsonous acid to the less toxic dimethylarsonic acid. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 11. [provided by RefSeq, Mar 2023]

N6AMT1 (HGNC:):

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=0.14418879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
N6AMT1	NM_013240.6	c.220A>G	p.Met74Val	missense_variant, splice_region_variant	2/6	ENST00000303775.10	NP_037372.4
N6AMT1	NM_182749.5	c.220A>G	p.Met74Val	missense_variant, splice_region_variant	2/5		NP_877426.4
N6AMT1	NR_047510.3	n.242A>G		splice_region_variant, non_coding_transcript_exon_variant	2/7
N6AMT1	XR_007067787.1	n.242A>G		splice_region_variant, non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
N6AMT1	ENST00000303775.10	c.220A>G	p.Met74Val	missense_variant, splice_region_variant	2/6	1	NM_013240.6	ENSP00000303584.5
N6AMT1	ENST00000351429.7	c.220A>G	p.Met74Val	missense_variant, splice_region_variant	2/5	1		ENSP00000286764.4
N6AMT1	ENST00000460212.1	n.220A>G		splice_region_variant, non_coding_transcript_exon_variant	2/7	1		ENSP00000436490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1429870 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 711928

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

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

Aug 01, 2024

The c.220A>G (p.M74V) alteration is located in exon 2 (coding exon 2) of the N6AMT1 gene. This alteration results from a A to G substitution at nucleotide position 220, causing the methionine (M) at amino acid position 74 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.043
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.0020	B;B
Vest4		0.30
MutPred		0.44		Loss of phosphorylation at Y73 (P = 0.1512);Loss of phosphorylation at Y73 (P = 0.1512);
MVP		0.10
MPC		0.15
ClinPred		0.35	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.076
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.080		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: chr21-30255308;