Genetic Variant METTL13:p.Tyr45Phe (chr1-171782101-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015935.5(METTL13):c.134A>T(p.Tyr45Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y45C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

METTL13
NM_015935.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.06

Publications

0 publications found

Variant links:

Genes affected

METTL13 (HGNC:24248): (methyltransferase 13, eEF1A N-terminus and K55) Predicted to enable methyltransferase activity. Involved in negative regulation of cell cycle G1/S phase transition and negative regulation of transcription by RNA polymerase II. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

METTL13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5 link	c.134A>T	p.Tyr45Phe	missense_variant	Exon 1 of 8	ENST00000361735.4	NP_057019.3	Q8N6R0-5C4B4C6
METTL13	NM_001007239.2 link	c.134A>T	p.Tyr45Phe	missense_variant	Exon 1 of 8		NP_001007240.1	Q8N6R0-1
METTL13	NM_014955.3 link	c.-106+306A>T		intron_variant	Intron 1 of 7		NP_055770.1	Q8N6R0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL13	ENST00000361735.4 link	c.134A>T	p.Tyr45Phe	missense_variant	Exon 1 of 8	1	NM_015935.5	ENSP00000354920.3	Q8N6R0-5
METTL13	ENST00000367737.9 link	c.134A>T	p.Tyr45Phe	missense_variant	Exon 1 of 8	1		ENSP00000356711.5	Q8N6R0-1
METTL13	ENST00000485629.1 link	n.246A>T		non_coding_transcript_exon_variant	Exon 2 of 4	5
METTL13	ENST00000362019.7 link	c.-106+306A>T		intron_variant	Intron 1 of 7	2		ENSP00000355393.3	Q8N6R0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111914

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000193

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

8.1

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.32

Sift

Benign

0.098

T;D

Sift4G

Uncertain

0.037

D;D

Polyphen

1.0

D;D

Vest4

0.56

MutPred

0.38

Gain of methylation at K44 (P = 0.0276);Gain of methylation at K44 (P = 0.0276);

MVP

0.79

MPC

0.79

ClinPred

0.98

GERP RS

5.5

PromoterAI

0.0028

Neutral

(source)

Varity_R

0.53

gMVP

0.35

Mutation Taster

=43/57

disease causing

(source)

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

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chr1-171782101-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over