Genetic Variant NM_022840.5:c.832A>G (chr18-2552762-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022840.5(METTL4):c.832A>G(p.Arg278Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,450,732 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.377

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044682264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5 link	c.832A>G	p.Arg278Gly	missense_variant, splice_region_variant	Exon 5 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.832A>G	p.Arg278Gly	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_022840.5	ENSP00000458290.1	Q8N3J2
METTL4	ENST00000573134.1 link	n.3133A>G		non_coding_transcript_exon_variant	Exon 3 of 7	1
METTL4	ENST00000319888.10 link	c.832A>G	p.Arg278Gly	missense_variant, splice_region_variant	Exon 5 of 8	5		ENSP00000320349.6	J3KNJ7
METTL4	ENST00000576251.5 link	c.25A>G	p.Arg9Gly	missense_variant, splice_region_variant	Exon 2 of 4	2		ENSP00000460774.1	I3L3W2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1450732

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33236

American (AMR)

AF:

0.00

AC:

AN:

44324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.000481

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

85362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104042

Other (OTH)

AF:

0.00

AC:

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jan 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.832A>G (p.R278G) alteration is located in exon 5 (coding exon 4) of the METTL4 gene. This alteration results from a A to G substitution at nucleotide position 832, causing the arginine (R) at amino acid position 278 to be replaced by a glycine (G). 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

0.054

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.00097

.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.24

.;N

PhyloP100

0.38

PrimateAI

Benign

0.30

PROVEAN

Benign

1.0

N;.

REVEL

Benign

0.035

Sift

Benign

0.78

T;.

Sift4G

Benign

0.63

T;T

Polyphen

0.0

.;B

Vest4

0.18

MutPred

0.50

Loss of stability (P = 0.0312);Loss of stability (P = 0.0312);

MVP

0.27

MPC

0.12

ClinPred

0.048

GERP RS

0.0042

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.080

gMVP

0.25

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.832A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over