Genetic Variant METTL4:p.Arg384Lys (chr18-2544683-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022840.5(METTL4):c.1151G>A(p.Arg384Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,611,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5 link	c.1151G>A	p.Arg384Lys	missense_variant	Exon 7 of 9	ENST00000574538.2	NP_073751.3	Q8N3J2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL4	ENST00000574538.2 link	c.1151G>A	p.Arg384Lys	missense_variant	Exon 7 of 9	1	NM_022840.5	ENSP00000458290.1	Q8N3J2
METTL4	ENST00000573134.1 link	n.3452G>A		non_coding_transcript_exon_variant	Exon 5 of 7	1
METTL4	ENST00000319888.10 link	c.1151G>A	p.Arg384Lys	missense_variant	Exon 7 of 8	5		ENSP00000320349.6	J3KNJ7
METTL4	ENST00000576251.5 link	c.267+2672G>A		intron_variant	Intron 3 of 3	2		ENSP00000460774.1	I3L3W2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250226

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459796

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726274

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33300

American (AMR)

AF:

0.0000677

AC:

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39586

South Asian (SAS)

AF:

0.00

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110986

Other (OTH)

AF:

0.00

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1151G>A (p.R384K) alteration is located in exon 7 (coding exon 6) of the METTL4 gene. This alteration results from a G to A substitution at nucleotide position 1151, causing the arginine (R) at amino acid position 384 to be replaced by a lysine (K). 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

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0041

.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.6

.;L

PhyloP100

3.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.23

Sift

Benign

0.081

T;.

Sift4G

Pathogenic

0.0

D;T

Polyphen

1.0

.;D

Vest4

0.29

MVP

0.78

MPC

0.30

ClinPred

0.75

GERP RS

4.8

Varity_R

0.67

gMVP

0.81

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 42

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

Publications

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18-2544683-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over