Variant 12-57769037-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005371.6(METTL1):c.790C>T(p.Leu264Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,457,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

METTL1
NM_005371.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

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]

METTL1 links:

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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=0.07967588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
METTL1	NM_005371.6 linkuse as main transcript	c.790C>T	p.Leu264Phe	missense_variant	6/6	ENST00000324871.12
METTL1	XM_005268873.3 linkuse as main transcript	c.661C>T	p.Leu221Phe	missense_variant	7/7
METTL1	XM_047428854.1 linkuse as main transcript	c.517C>T	p.Leu173Phe	missense_variant	5/5
METTL1	NM_023033.4 linkuse as main transcript	c.*137C>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL1	ENST00000324871.12 linkuse as main transcript	c.790C>T	p.Leu264Phe	missense_variant	6/6	1	NM_005371.6	P1	Q9UBP6-1
METTL1	ENST00000257848.7 linkuse as main transcript	c.*137C>T		3_prime_UTR_variant	5/5	1			Q9UBP6-2
METTL1	ENST00000547653.1 linkuse as main transcript	c.*137C>T		3_prime_UTR_variant	3/3	3
METTL1	ENST00000548504.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251440

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1457970

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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 submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.790C>T (p.L264F) alteration is located in exon 6 (coding exon 6) of the METTL1 gene. This alteration results from a C to T substitution at nucleotide position 790, causing the leucine (L) at amino acid position 264 to be replaced by a phenylalanine (F). 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

0.081

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.076

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.64

M_CAP

Benign

0.0037

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.60

REVEL

Benign

0.060

Sift

Benign

0.26

Sift4G

Benign

0.098

Polyphen

0.0010

Vest4

0.079

MutPred

0.36

Gain of catalytic residue at S269 (P = 0.0026);

MVP

0.14

MPC

0.22

ClinPred

0.029

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over