Genetic Variant NM_005371.6:c.326G>T (chr12-57769905-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005371.6(METTL1):c.326G>T(p.Arg109Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

METTL1
NM_005371.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.89

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

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.326G>T	p.Arg109Leu	missense	Exon 3 of 6	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.275-227G>T		intron	N/A	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.326G>T	p.Arg109Leu	missense	Exon 3 of 6	ENSP00000314441.7	Q9UBP6-1
METTL1	ENST00000257848.7	TSL:1	c.275-227G>T		intron	N/A	ENSP00000257848.7	Q9UBP6-2
METTL1	ENST00000966255.1		c.302G>T	p.Arg101Leu	missense	Exon 3 of 6	ENSP00000636314.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000481

AC:

AN:

249444

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000958

AC:

AN:

1461028

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.000291

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111604

Other (OTH)

AF:

0.0000166

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.7

PhyloP100

6.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.97

MutPred

0.81

Gain of catalytic residue at K111 (P = 0.0011)

MVP

0.84

MPC

0.86

ClinPred

0.99

GERP RS

4.9

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.82

gMVP

0.93

Mutation Taster

=20/80

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over