chr12-57771977-C-T

Variant summary

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

The NM_005371.6(METTL1):​c.107G>A​(p.Arg36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,366,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

METTL1
NM_005371.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
Variant links:
Genes affected
METTL1 (HGNC:7030): (methyltransferase 1, tRNA methylguanosine) This gene is similar in sequence to the S. cerevisiae YDL201w gene. The gene product contains a conserved S-adenosylmethionine-binding motif and is inactivated by phosphorylation. Alternative splice variants encoding different protein isoforms have been described for this gene. A pseudogene has been identified on chromosome X. [provided by RefSeq, Jul 2008]
EEF1AKMT3 (HGNC:24936): (EEF1A lysine methyltransferase 3) Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Located in several cellular components, including centrosome; chromosome; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

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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=0.11479634).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
METTL1NM_005371.6 linkuse as main transcriptc.107G>A p.Arg36His missense_variant 1/6 ENST00000324871.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
METTL1ENST00000324871.12 linkuse as main transcriptc.107G>A p.Arg36His missense_variant 1/61 NM_005371.6 P1Q9UBP6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000146
AC:
2
AN:
1366568
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
674606
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000395
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:
9.33e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 GeneticsAug 17, 2022The c.107G>A (p.R36H) alteration is located in exon 1 (coding exon 1) of the METTL1 gene. This alteration results from a G to A substitution at nucleotide position 107, causing the arginine (R) at amino acid position 36 to be replaced by a histidine (H). 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
0.078
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.067
T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.20
N
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.34
N;N
MutationTaster
Benign
0.97
D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
0.35
N;N
REVEL
Benign
0.027
Sift
Benign
0.060
T;T
Sift4G
Benign
0.093
T;T
Polyphen
0.0020
B;.
Vest4
0.087
MutPred
0.40
Gain of catalytic residue at L35 (P = 0.0021);Gain of catalytic residue at L35 (P = 0.0021);
MVP
0.53
MPC
0.24
ClinPred
0.78
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.42

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

LitVar

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

Other links and lift over

dbSNP: rs995455744; hg19: chr12-58165760; API