Genetic Variant METTL13:p.Val146Ala (chr1-171784023-T-C) – 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.437T>C(p.Val146Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

METTL13
NM_015935.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

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.437T>C	p.Val146Ala	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3	Q8N6R0-5C4B4C6
METTL13	NM_014955.3 link	c.179T>C	p.Val60Ala	missense_variant	Exon 2 of 8		NP_055770.1	Q8N6R0-3
METTL13	NM_001007239.2 link	c.437T>C	p.Val146Ala	missense_variant	Exon 2 of 8		NP_001007240.1	Q8N6R0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL13	ENST00000361735.4 link	c.437T>C	p.Val146Ala	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3	Q8N6R0-5
METTL13	ENST00000367737.9 link	c.437T>C	p.Val146Ala	missense_variant	Exon 2 of 8	1		ENSP00000356711.5	Q8N6R0-1
METTL13	ENST00000362019.7 link	c.179T>C	p.Val60Ala	missense_variant	Exon 2 of 8	2		ENSP00000355393.3	Q8N6R0-3
METTL13	ENST00000485629.1 link	n.549T>C		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.437T>C (p.V146A) alteration is located in exon 2 (coding exon 2) of the METTL13 gene. This alteration results from a T to C substitution at nucleotide position 437, causing the valine (V) at amino acid position 146 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.5

.;L;L

PhyloP100

7.5

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0060

D;T;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.0010, 0.70

.;B;P

Vest4

0.63

MVP

0.72

MPC

0.44

ClinPred

0.97

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.37

gMVP

0.65

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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chr1-171784023-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over