dbSNP rs2072182124: METTL4:p.Arg278Gly (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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rs2072182124

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