21-28885331-G-C

Position:

• chr21-28885331-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013240.6(N6AMT1):​c.15C>G​(p.Asn5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: N6AMT1 NM_013240.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -7.02

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042200327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
N6AMT1	NM_013240.6	c.15C>G	p.Asn5Lys	missense_variant	1/6	ENST00000303775.10	NP_037372.4
N6AMT1	NM_182749.5	c.15C>G	p.Asn5Lys	missense_variant	1/5		NP_877426.4
N6AMT1	NR_047510.3	n.37C>G		non_coding_transcript_exon_variant	1/7
N6AMT1	XR_007067787.1	n.37C>G		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
N6AMT1	ENST00000303775.10	c.15C>G	p.Asn5Lys	missense_variant	1/6	1	NM_013240.6	ENSP00000303584	P1
N6AMT1	ENST00000351429.7	c.15C>G	p.Asn5Lys	missense_variant	1/5	1		ENSP00000286764
N6AMT1	ENST00000460212.1	c.15C>G	p.Asn5Lys	missense_variant, NMD_transcript_variant	1/7	1		ENSP00000436490

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428382 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 705598

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: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Jun 18, 2024

The c.15C>G (p.N5K) alteration is located in exon 1 (coding exon 1) of the N6AMT1 gene. This alteration results from a C to G substitution at nucleotide position 15, causing the asparagine (N) at amino acid position 5 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	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0030
DANN	Benign	0.48
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.24	.;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.013
Sift	Benign	0.73	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0030	B;B
Vest4		0.11
MutPred		0.27		Gain of methylation at N5 (P = 0.0077);Gain of methylation at N5 (P = 0.0077);
MVP		0.092
MPC		0.17
ClinPred		0.048	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1421697475; hg19: chr21-30257653;