18-2547501-G-T

Variant names:

• chr18-2547501-G-T
• rs2677879
• NM_022840.5:c.928C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022840.5(METTL4):​c.928C>A​(p.Gln310Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,594,982 control chromosomes in the GnomAD database, including 307,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.65 (32848 hom., cov: 32)
  • Exomes 𝑓: 0.61 (274489 hom.)
• Consequence: METTL4 NM_022840.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 35 publications found

Genes affected

METTL4 (HGNC:24726): (methyltransferase 4, N6-adenosine) Enables RNA methyltransferase activity and site-specific DNA-methyltransferase (adenine-specific) activity. Involved in nucleic acid metabolic process; regulation of RNA metabolic process; and regulation of mitochondrial DNA replication. Located in cytosol; mitochondrial matrix; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.104673E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5	c.928C>A	p.Gln310Lys	missense_variant	Exon 6 of 9	ENST00000574538.2	NP_073751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL4	ENST00000574538.2	c.928C>A	p.Gln310Lys	missense_variant	Exon 6 of 9	1	NM_022840.5	ENSP00000458290.1
METTL4	ENST00000573134.1	n.3229C>A		non_coding_transcript_exon_variant	Exon 4 of 7	1
METTL4	ENST00000319888.10	c.928C>A	p.Gln310Lys	missense_variant	Exon 6 of 8	5		ENSP00000320349.6
METTL4	ENST00000576251.5	c.121C>A	p.Gln41Lys	missense_variant	Exon 3 of 4	2		ENSP00000460774.1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98399 AN: 151948 Hom.: 32810 Cov.: 32

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.644

GnomAD2 exomes AF: 0.579 AC: 137632 AN: 237672 AF XY: 0.583

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.613 AC: 884069 AN: 1442916 Hom.: 274489 Cov.: 38 AF XY: 0.612 AC XY: 439118 AN XY: 717268

African (AFR) AF: 0.810 AC: 26258 AN: 32416

American (AMR) AF: 0.412 AC: 16717 AN: 40538

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 17974 AN: 25318

East Asian (EAS) AF: 0.375 AC: 14788 AN: 39460

South Asian (SAS) AF: 0.582 AC: 48410 AN: 83216

European-Finnish (FIN) AF: 0.581 AC: 30846 AN: 53110

Middle Eastern (MID) AF: 0.650 AC: 3692 AN: 5682

European-Non Finnish (NFE) AF: 0.624 AC: 689019 AN: 1103618

Other (OTH) AF: 0.611 AC: 36365 AN: 59558

GnomAD4 genome AF: 0.648 AC: 98486 AN: 152066 Hom.: 32848 Cov.: 32 AF XY: 0.640 AC XY: 47582 AN XY: 74318

African (AFR) AF: 0.797 AC: 33070 AN: 41492

American (AMR) AF: 0.517 AC: 7895 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 2410 AN: 3468

East Asian (EAS) AF: 0.367 AC: 1895 AN: 5160

South Asian (SAS) AF: 0.582 AC: 2808 AN: 4824

European-Finnish (FIN) AF: 0.566 AC: 5987 AN: 10572

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42230 AN: 67960

Other (OTH) AF: 0.645 AC: 1362 AN: 2110

Alfa AF: 0.624 Hom.: 91913

Bravo AF: 0.646

TwinsUK AF: 0.634 AC: 2350

ALSPAC AF: 0.629 AC: 2424

ESP6500AA AF: 0.794 AC: 3499

ESP6500EA AF: 0.621 AC: 5344

ExAC AF: 0.585 AC: 70968

Asia WGS AF: 0.523 AC: 1819 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.0012	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.039	T;T
MetaRNN	Benign	7.1e-7	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.1	.;N
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.4	N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.068
MPC		0.12
ClinPred		0.0046	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.53
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2677879; hg19: chr18-2547500; COSMIC: COSV60603634;