18-2544270-C-T

Variant summary

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

The NM_022840.5(METTL4):​c.1198G>A​(p.Val400Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.264
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]

Genome browser will be placed here

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=0.06926754).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
METTL4NM_022840.5 linkuse as main transcriptc.1198G>A p.Val400Met missense_variant 8/9 ENST00000574538.2 NP_073751.3 Q8N3J2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
METTL4ENST00000574538.2 linkuse as main transcriptc.1198G>A p.Val400Met missense_variant 8/91 NM_022840.5 ENSP00000458290.1 Q8N3J2
METTL4ENST00000573134.1 linkuse as main transcriptn.3499G>A non_coding_transcript_exon_variant 6/71
METTL4ENST00000319888.10 linkuse as main transcriptc.1181+383G>A intron_variant 5 ENSP00000320349.6 J3KNJ7
METTL4ENST00000576251.5 linkuse as main transcriptc.267+3085G>A intron_variant 2 ENSP00000460774.1 I3L3W2

Frequencies

GnomAD3 genomes
AF:
0.0000461
AC:
7
AN:
151976
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
250304
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135348
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1459864
Hom.:
0
Cov.:
29
AF XY:
0.0000193
AC XY:
14
AN XY:
726310
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
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:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000461
AC:
7
AN:
151976
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74204
show subpopulations
Gnomad4 AFR
AF:
0.0000967
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsMay 30, 2023The c.1198G>A (p.V400M) alteration is located in exon 8 (coding exon 7) of the METTL4 gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the valine (V) at amino acid position 400 to be replaced by a methionine (M). 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
0.086
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
9.8
DANN
Benign
0.78
DEOGEN2
Benign
0.0052
T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.069
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L
PrimateAI
Benign
0.32
T
Sift4G
Benign
0.28
T
Polyphen
0.18
B
Vest4
0.12
MVP
0.25
MPC
0.11
ClinPred
0.034
T
GERP RS
3.0
Varity_R
0.041
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368748723; hg19: chr18-2544269; COSMIC: COSV60603095; API