18-2554759-C-A

Position:

• chr18-2554759-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022840.5(METTL4):​c.739G>T​(p.Val247Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: METTL4 NM_022840.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.733

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]

METTL4 (HGNC:):

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=0.07548204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL4	NM_022840.5	c.739G>T	p.Val247Leu	missense_variant	4/9	ENST00000574538.2	NP_073751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL4	ENST00000574538.2	c.739G>T	p.Val247Leu	missense_variant	4/9	1	NM_022840.5	ENSP00000458290.1
METTL4	ENST00000573134.1	n.1136G>T		non_coding_transcript_exon_variant	3/7	1
METTL4	ENST00000319888.10	c.739G>T	p.Val247Leu	missense_variant	4/8	5		ENSP00000320349.6
METTL4	ENST00000577166.5	c.*27G>T		downstream_gene_variant		4		ENSP00000458415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 02, 2021

The c.739G>T (p.V247L) alteration is located in exon 4 (coding exon 3) of the METTL4 gene. This alteration results from a G to T substitution at nucleotide position 739, causing the valine (V) at amino acid position 247 to be replaced by a leucine (L). 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	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.0032	.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	.;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N;.
REVEL	Benign	0.030
Sift	Benign	0.15	T;.
Sift4G	Benign	0.33	T;T
Polyphen		0.0020	.;B
Vest4		0.10
MutPred		0.41		Loss of catalytic residue at V247 (P = 0.0098);Loss of catalytic residue at V247 (P = 0.0098);
MVP		0.23
MPC		0.094
ClinPred		0.19	T
GERP RS		3.5
Varity_R		0.045
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-2554758;