Variant 18-2554791-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022840.5(METTL4):c.707G>T(p.Arg236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.24721375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL4	NM_022840.5 linkuse as main transcript	c.707G>T	p.Arg236Leu	missense_variant	4/9	ENST00000574538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
METTL4	ENST00000574538.2 linkuse as main transcript	c.707G>T	p.Arg236Leu	missense_variant	4/9	1	NM_022840.5	P1
METTL4	ENST00000573134.1 linkuse as main transcript	n.1104G>T		non_coding_transcript_exon_variant	3/7	1
METTL4	ENST00000319888.10 linkuse as main transcript	c.707G>T	p.Arg236Leu	missense_variant	4/8	5
METTL4	ENST00000577166.5 linkuse as main transcript	c.266G>T	p.Arg89Leu	missense_variant	4/4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.707G>T (p.R236L) 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 707, causing the arginine (R) at amino acid position 236 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

0.24

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0096

.;T;T

Eigen

Benign

-0.052

Eigen_PC

Benign

-0.068

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.91

D;D;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;M;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.2

N;.;.

REVEL

Benign

0.12

Sift

Benign

0.26

T;.;.

Sift4G

Benign

0.20

T;T;.

Polyphen

0.86

.;P;.

Vest4

0.52

MutPred

0.47

Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;

MVP

0.62

MPC

0.17

ClinPred

0.88

GERP RS

3.1

Varity_R

0.088

gMVP

0.51

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over