Genetic Variant NM_022840.5:c.916C>A (chr18-2547513-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022840.5(METTL4):c.916C>A(p.Pro306Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,583,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P306S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13429317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5 link	c.916C>A	p.Pro306Thr	missense_variant	Exon 6 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.916C>A	p.Pro306Thr	missense_variant	Exon 6 of 9	1	NM_022840.5	ENSP00000458290.1	Q8N3J2
METTL4	ENST00000573134.1 link	n.3217C>A		non_coding_transcript_exon_variant	Exon 4 of 7	1
METTL4	ENST00000319888.10 link	c.916C>A	p.Pro306Thr	missense_variant	Exon 6 of 8	5		ENSP00000320349.6	J3KNJ7
METTL4	ENST00000576251.5 link	c.109C>A	p.Pro37Thr	missense_variant	Exon 3 of 4	2		ENSP00000460774.1	I3L3W2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1431062

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

711228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31782

American (AMR)

AF:

0.00

AC:

AN:

36750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24470

East Asian (EAS)

AF:

0.00

AC:

AN:

39326

South Asian (SAS)

AF:

0.00

AC:

AN:

81106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100176

Other (OTH)

AF:

0.00

AC:

AN:

59008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0012

.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0070

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.60

N;.

REVEL

Benign

0.036

Sift

Benign

0.19

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.77

.;P

Vest4

0.30

MutPred

0.44

Gain of catalytic residue at Q310 (P = 0.0769);Gain of catalytic residue at Q310 (P = 0.0769);

MVP

0.53

MPC

0.12

ClinPred

0.30

GERP RS

2.3

Varity_R

0.11

gMVP

0.43

Mutation Taster

=91/9

polymorphism

(source)

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

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NM_022840.5:c.916C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over