Genetic Variant METTL13:p.Asp78Tyr (chr1-171783818-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015935.5(METTL13):c.232G>T(p.Asp78Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D78N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

METTL13
NM_015935.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.40

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5 link	c.232G>T	p.Asp78Tyr	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3	Q8N6R0-5C4B4C6
METTL13	NM_001007239.2 link	c.232G>T	p.Asp78Tyr	missense_variant	Exon 2 of 8		NP_001007240.1	Q8N6R0-1
METTL13	NM_014955.3 link	c.-27G>T		5_prime_UTR_variant	Exon 2 of 8		NP_055770.1	Q8N6R0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL13	ENST00000361735.4 link	c.232G>T	p.Asp78Tyr	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3	Q8N6R0-5
METTL13	ENST00000367737.9 link	c.232G>T	p.Asp78Tyr	missense_variant	Exon 2 of 8	1		ENSP00000356711.5	Q8N6R0-1
METTL13	ENST00000485629.1 link	n.344G>T		non_coding_transcript_exon_variant	Exon 3 of 4	5
METTL13	ENST00000362019.7 link	c.-27G>T		5_prime_UTR_variant	Exon 2 of 8	2		ENSP00000355393.3	Q8N6R0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.7

H;H

PhyloP100

9.4

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.2

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.90

Loss of catalytic residue at D78 (P = 0.0322);Loss of catalytic residue at D78 (P = 0.0322);

MVP

0.97

MPC

0.92

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

0.91

Mutation Taster

=6/94

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over