Variant 12-57769580-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_023033.4(METTL1):c.373C>T(p.Arg125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000413 in 1,551,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

METTL1
NM_023033.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.19

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:

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=0.14373028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL1	NM_005371.6 linkuse as main transcript	c.558C>T	p.Tyr186Tyr	synonymous_variant	4/6	ENST00000324871.12	NP_005362.3	Q9UBP6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL1	ENST00000324871.12 linkuse as main transcript	c.558C>T	p.Tyr186Tyr	synonymous_variant	4/6	1	NM_005371.6	ENSP00000314441.7		Q9UBP6-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000488

AC:

AN:

205100

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

108036

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000109

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000407

AC:

AN:

1399256

Hom.:

Cov.:

AF XY:

0.0000349

AC XY:

AN XY:

687588

show subpopulations

Gnomad4 AFR exome

AF:

0.0000938

Gnomad4 AMR exome

AF:

0.000128

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000177

Gnomad4 NFE exome

AF:

0.0000325

Gnomad4 OTH exome

AF:

0.0000695

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000416

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

9.2

DANN

Uncertain

0.98

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.49

M_CAP

Benign

0.0029

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.91

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.38

MutPred

0.55

Gain of catalytic residue at G130 (P = 0);

MVP

0.46

ClinPred

0.11

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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