21-28878251-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013240.6(N6AMT1):c.479C>T(p.Pro160Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00778 in 1,606,370 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (53 hom.)
• Consequence: N6AMT1 NM_013240.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.45

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038720965).
• BP6: Variant 21-28878251-G-A is Benign according to our data. Variant chr21-28878251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2652578.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
N6AMT1	NM_013240.6	c.479C>T	p.Pro160Leu	missense_variant	5/6	ENST00000303775.10
N6AMT1	NM_182749.5	c.395C>T	p.Pro132Leu	missense_variant	4/5
N6AMT1	NR_047510.3	n.501C>T		non_coding_transcript_exon_variant	5/7
N6AMT1	XR_007067787.1	n.501C>T		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
N6AMT1	ENST00000303775.10	c.479C>T	p.Pro160Leu	missense_variant	5/6	1	NM_013240.6	P1
N6AMT1	ENST00000351429.7	c.395C>T	p.Pro132Leu	missense_variant	4/5	1
N6AMT1	ENST00000460212.1	c.479C>T	p.Pro160Leu	missense_variant, NMD_transcript_variant	5/7	1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152158 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00514 AC: 1264 AN: 245706 Hom.: 2 AF XY: 0.00526 AC XY: 699 AN XY: 132924

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000581

Gnomad FIN exome AF: 0.00572

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.00584

GnomAD4 exome AF: 0.00801 AC: 11650 AN: 1454094 Hom.: 53 Cov.: 30 AF XY: 0.00786 AC XY: 5685 AN XY: 723556

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000706

Gnomad4 FIN exome AF: 0.00571

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00561 AC: 854 AN: 152276 Hom.: 4 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74456

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00751 Hom.: 11

Bravo AF: 0.00480

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00536 AC: 651

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

N6AMT1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.14
Sift	Benign	0.041	D;D
Sift4G	Benign	0.081	T;T
Polyphen		0.0030	B;B
Vest4		0.13
MVP		0.30
MPC		0.15
ClinPred		0.039	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.53

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: rs61735764; hg19: chr21-30250573; COSMIC: COSV99053391;