Genetic Variant NM_005371.6:c.566G>A (chr12-57769572-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005371.6(METTL1):c.566G>A(p.Arg189Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,400,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

METTL1
NM_005371.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21953762).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005371.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL1	NM_005371.6	MANE Select	c.566G>A	p.Arg189Lys	missense	Exon 4 of 6	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.381G>A	p.Lys127Lys	synonymous	Exon 3 of 5	NP_075422.3	Q9UBP6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METTL1	ENST00000324871.12	TSL:1 MANE Select	c.566G>A	p.Arg189Lys	missense	Exon 4 of 6	ENSP00000314441.7	Q9UBP6-1
METTL1	ENST00000257848.7	TSL:1	c.381G>A	p.Lys127Lys	synonymous	Exon 3 of 5	ENSP00000257848.7	Q9UBP6-2
METTL1	ENST00000966255.1		c.542G>A	p.Arg181Lys	missense	Exon 4 of 6	ENSP00000636314.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1400346

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32044

American (AMR)

AF:

0.00

AC:

AN:

39094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21836

East Asian (EAS)

AF:

0.00

AC:

AN:

39138

South Asian (SAS)

AF:

0.00

AC:

AN:

75870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078462

Other (OTH)

AF:

0.00

AC:

AN:

57620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.12

Eigen

Benign

0.028

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0054

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

PhyloP100

4.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.95

REVEL

Benign

0.075

Sift

Benign

0.28

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.45

MutPred

0.47

Gain of catalytic residue at V190 (P = 0.0017)

MVP

0.38

MPC

0.20

ClinPred

0.96

GERP RS

4.8

PromoterAI

-0.0084

Neutral

(source)

Varity_R

0.38

gMVP

0.79

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over