rs2677879

chr18-2547501-G-Cchr18-2547501-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q310K) has been classified as Likely benign.

• 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL4	NM_022840.5	c.928C>G	p.Gln310Glu	missense_variant	6/9	ENST00000574538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL4	ENST00000574538.2	c.928C>G	p.Gln310Glu	missense_variant	6/9	1	NM_022840.5	P1
METTL4	ENST00000573134.1	n.3229C>G		non_coding_transcript_exon_variant	4/7	1
METTL4	ENST00000319888.10	c.928C>G	p.Gln310Glu	missense_variant	6/8	5
METTL4	ENST00000576251.5	c.124C>G	p.Gln42Glu	missense_variant	3/4	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.46	N;.
REVEL	Benign	0.072
Sift	Benign	0.17	T;.
Sift4G	Uncertain	0.031	D;T
Polyphen		0.014	.;B
Vest4		0.13
MutPred		0.40		Loss of glycosylation at P315 (P = 0.1382);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2677879; hg19: chr18-2547500;