Genetic Variant METTL15:p.Tyr40Phe (chr11-28113453-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001113528.2(METTL15):c.119A>T(p.Tyr40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,459,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. Y40C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

METTL15
NM_001113528.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.165

Publications

0 publications found

Variant links:

Genes affected

METTL15 (HGNC:26606): (methyltransferase 15, mitochondrial 12S rRNA N4-cytidine) Predicted to enable rRNA (cytosine-N4-)-methyltransferase activity. Predicted to be involved in rRNA base methylation. Predicted to be located in mitochondrial matrix. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

METTL15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060465127).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113528.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METTL15	NM_001113528.2	MANE Select	c.119A>T	p.Tyr40Phe	missense	Exon 3 of 7	NP_001107000.1	A6NJ78-1
METTL15	NM_001297775.2		c.119A>T	p.Tyr40Phe	missense	Exon 3 of 7	NP_001284704.1	A6NJ78-4
METTL15	NM_152636.3		c.119A>T	p.Tyr40Phe	missense	Exon 3 of 8	NP_689849.2	A6NJ78-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METTL15	ENST00000407364.8	TSL:5 MANE Select	c.119A>T	p.Tyr40Phe	missense	Exon 3 of 7	ENSP00000384369.3	A6NJ78-1
METTL15	ENST00000406787.7	TSL:1	c.119A>T	p.Tyr40Phe	missense	Exon 3 of 7	ENSP00000385507.3	A6NJ78-4
METTL15	ENST00000437814.1	TSL:1	n.119A>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000392806.1	A6NJ78-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250058

AF XY:

0.00000738

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1459542

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4420

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111514

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

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

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.32

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.024

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.021

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0070

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

-0.17

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.31

REVEL

Benign

0.0080

Sift

Benign

0.14

Sift4G

Benign

0.62

Polyphen

0.59

Vest4

0.23

MVP

0.061

MPC

0.071

ClinPred

0.059

GERP RS

-1.2

Varity_R

0.046

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over