Genetic Variant METTL2B:p.Ala274Pro (chr7-128498046-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018396.3(METTL2B):c.820G>C(p.Ala274Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

METTL2B
NM_018396.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.33

Publications

0 publications found

Variant links:

Genes affected

METTL2B (HGNC:18272): (methyltransferase 2B, tRNA N3-cytidine) This gene is a member of a family of methyltransferases that share homology with, but are distinct from, the UbiE family of methyltransferases. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

METTL2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018396.3. 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
	METTL2B	NM_018396.3	MANE Select	c.820G>C	p.Ala274Pro	missense	Exon 7 of 9	NP_060866.2	Q6P1Q9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METTL2B	ENST00000262432.13	TSL:1 MANE Select	c.820G>C	p.Ala274Pro	missense	Exon 7 of 9	ENSP00000262432.9	Q6P1Q9-1
METTL2B	ENST00000482555.5	TSL:1	n.1063G>C		non_coding_transcript_exon	Exon 6 of 8
METTL2B	ENST00000930216.1		c.820G>C	p.Ala274Pro	missense	Exon 7 of 10	ENSP00000600275.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251468

AF XY:

0.00000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111796

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0028

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.3

PhyloP100

4.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

REVEL

Benign

0.27

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.017

Polyphen

0.97

Vest4

0.85

MutPred

0.77

Loss of MoRF binding (P = 0.0471)

MVP

0.46

MPC

0.40

ClinPred

0.85

GERP RS

3.4

Varity_R

0.94

gMVP

0.89

Mutation Taster

=76/24

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