18-2547492-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022840.5(METTL4):ā€‹c.937C>Gā€‹(p.Pro313Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,603,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

METTL4
NM_022840.5 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.85
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
METTL4NM_022840.5 linkuse as main transcriptc.937C>G p.Pro313Ala missense_variant 6/9 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.937C>G p.Pro313Ala missense_variant 6/91 NM_022840.5 ENSP00000458290.1 Q8N3J2
METTL4ENST00000573134.1 linkuse as main transcriptn.3238C>G non_coding_transcript_exon_variant 4/71
METTL4ENST00000319888.10 linkuse as main transcriptc.937C>G p.Pro313Ala missense_variant 6/85 ENSP00000320349.6 J3KNJ7
METTL4ENST00000576251.5 linkuse as main transcriptc.130C>G p.Pro44Ala missense_variant 3/42 ENSP00000460774.1 I3L3W2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152168
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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
GnomAD3 exomes
AF:
0.00000827
AC:
2
AN:
241946
Hom.:
0
AF XY:
0.00000763
AC XY:
1
AN XY:
131006
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000630
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1451330
Hom.:
0
Cov.:
30
AF XY:
0.00000139
AC XY:
1
AN XY:
721802
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000475
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152286
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
ExAC
AF:
0.00000824
AC:
1

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 GeneticsOct 27, 2023The c.937C>G (p.P313A) alteration is located in exon 6 (coding exon 5) of the METTL4 gene. This alteration results from a C to G substitution at nucleotide position 937, causing the proline (P) at amino acid position 313 to be replaced by an alanine (A). 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
0.33
BayesDel_addAF
Uncertain
0.032
T
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.18
.;T
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.68
D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Pathogenic
3.6
.;H
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-7.3
D;.
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.62
MVP
0.70
MPC
0.48
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.89
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs200692616; hg19: chr18-2547491; API