chr18-2544681-C-A

Position:

• chr18-2544681-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.1153G>T​(p.Val385Phe) 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. 14/21 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: 0.124

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=0.15223709).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL4	NM_022840.5	c.1153G>T	p.Val385Phe	missense_variant	7/9	ENST00000574538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL4	ENST00000574538.2	c.1153G>T	p.Val385Phe	missense_variant	7/9	1	NM_022840.5	P1
METTL4	ENST00000573134.1	n.3454G>T		non_coding_transcript_exon_variant	5/7	1
METTL4	ENST00000319888.10	c.1153G>T	p.Val385Phe	missense_variant	7/8	5
METTL4	ENST00000576251.5	c.269+2674G>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 03, 2022

The c.1153G>T (p.V385F) alteration is located in exon 7 (coding exon 6) of the METTL4 gene. This alteration results from a G to T substitution at nucleotide position 1153, causing the valine (V) at amino acid position 385 to be replaced by a phenylalanine (F). 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	0.065
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0041	.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	0.87	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.72	N;.
REVEL	Benign	0.046
Sift	Benign	0.20	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.079	.;B
Vest4		0.23
MutPred		0.61		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.52
MPC		0.14
ClinPred		0.17	T
GERP RS		1.0
Varity_R		0.12
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: chr18-2544680;