18-2547474-C-T

Variant names:

• chr18-2547474-C-T
• NM_022840.5:c.955G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022840.5(METTL4):​c.955G>A​(p.Ala319Thr) 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. 13/22 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: 3.16
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37451878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5	c.955G>A	p.Ala319Thr	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.955G>A	p.Ala319Thr	missense_variant	Exon 6 of 9	1	NM_022840.5	ENSP00000458290.1
METTL4	ENST00000573134.1	n.3256G>A		non_coding_transcript_exon_variant	Exon 4 of 7	1
METTL4	ENST00000319888.10	c.955G>A	p.Ala319Thr	missense_variant	Exon 6 of 8	5		ENSP00000320349.6
METTL4	ENST00000576251.5	c.148G>A	p.Ala50Thr	missense_variant	Exon 3 of 4	2		ENSP00000460774.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.955G>A (p.A319T) alteration is located in exon 6 (coding exon 5) of the METTL4 gene. This alteration results from a G to A substitution at nucleotide position 955, causing the alanine (A) at amino acid position 319 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0022	.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.16
Sift	Benign	0.091	T;.
Sift4G	Uncertain	0.011	D;T
Polyphen		1.0	.;D
Vest4		0.42
MutPred		0.56		Gain of methylation at K316 (P = 0.0976);Gain of methylation at K316 (P = 0.0976);
MVP		0.66
MPC		0.40
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.53

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

Other links and lift over

hg19: chr18-2547473;