21-28885257-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013240.6(N6AMT1):c.89T>A(p.Phe30Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: N6AMT1 NM_013240.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34379232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
N6AMT1	NM_013240.6	c.89T>A	p.Phe30Tyr	missense_variant	1/6	ENST00000303775.10
N6AMT1	NM_182749.5	c.89T>A	p.Phe30Tyr	missense_variant	1/5
N6AMT1	NR_047510.3	n.111T>A		non_coding_transcript_exon_variant	1/7
N6AMT1	XR_007067787.1	n.111T>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
N6AMT1	ENST00000303775.10	c.89T>A	p.Phe30Tyr	missense_variant	1/6	1	NM_013240.6	P1
N6AMT1	ENST00000351429.7	c.89T>A	p.Phe30Tyr	missense_variant	1/5	1
N6AMT1	ENST00000460212.1	c.89T>A	p.Phe30Tyr	missense_variant, NMD_transcript_variant	1/7	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Apr 17, 2023

The c.89T>A (p.F30Y) alteration is located in exon 1 (coding exon 1) of the N6AMT1 gene. This alteration results from a T to A substitution at nucleotide position 89, causing the phenylalanine (F) at amino acid position 30 to be replaced by a tyrosine (Y). 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	0.28
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.17
Sift	Benign	0.036	D;D
Sift4G	Benign	0.090	T;T
Polyphen		0.54	P;P
Vest4		0.44
MutPred		0.68		Gain of phosphorylation at F30 (P = 0.0429);Gain of phosphorylation at F30 (P = 0.0429);
MVP		0.14
MPC		0.47
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1989625174; hg19: chr21-30257579;