chr18-2547501-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022840.5(METTL4):​c.928C>G​(p.Gln310Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,732 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09264445).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022840.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL4	NM_022840.5	MANE Select	c.928C>G	p.Gln310Glu	missense	Exon 6 of 9	NP_073751.3
	METTL4	NM_001308401.2		c.928C>G	p.Gln310Glu	missense	Exon 6 of 8	NP_001295330.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL4	ENST00000574538.2	TSL:1 MANE Select	c.928C>G	p.Gln310Glu	missense	Exon 6 of 9	ENSP00000458290.1
	METTL4	ENST00000573134.1	TSL:1	n.3229C>G		non_coding_transcript_exon	Exon 4 of 7
	METTL4	ENST00000319888.10	TSL:5	c.928C>G	p.Gln310Glu	missense	Exon 6 of 8	ENSP00000320349.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444732 Hom.: 0 Cov.: 38 AF XY: 0.00000139 AC XY: 1 AN XY: 718212

African (AFR) AF: 0.00 AC: 0 AN: 32454

American (AMR) AF: 0.00 AC: 0 AN: 40638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 83380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104966

Other (OTH) AF: 0.00 AC: 0 AN: 59620

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.18	N
PhyloP100		2.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.072
Sift	Benign	0.17	T
Sift4G	Uncertain	0.031	D
Polyphen		0.014	B
Vest4		0.13
MutPred		0.40		Loss of glycosylation at P315 (P = 0.1382)
MVP		0.25
MPC		0.11
ClinPred		0.54	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.63
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;