Genetic Variant METTL23:p.Gln133Glu (chr17-76733367-C-G) – 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_001080510.5(METTL23):c.397C>G(p.Gln133Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

METTL23
NM_001080510.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.57

Publications

0 publications found

Variant links:

Genes affected

METTL23 (HGNC:26988): (methyltransferase 23, arginine) The protein encoded by this gene functions as a transcription factor regulator in the transcriptional pathway for human cognition. It is a partner of the alpha subunit of the GA-binding protein transcription factor. Mutations in this gene cause mild autosomal recessive intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

METTL23 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 44
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

METTL23 links:

ENSG00000267168 (HGNC:):

ENSG00000267168 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
METTL23	NM_001080510.5 link	c.397C>G	p.Gln133Glu	missense_variant	Exon 4 of 5	ENST00000341249.11	NP_001073979.3	Q86XA0-1A0A024R8M5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL23	ENST00000341249.11 link	c.397C>G	p.Gln133Glu	missense_variant	Exon 4 of 5	1	NM_001080510.5	ENSP00000341543.5		Q86XA0-1
ENSG00000267168	ENST00000587459.1 link	c.238+152C>G		intron_variant	Intron 1 of 1	5		ENSP00000466829.1		K7EN84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111808

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Benign

0.29

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

.;T;.;.;.;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

T;D;T;D;.;T;D;.;T;.;.;D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

.;L;.;.;.;.;.;.;.;.;L;.;.

PhyloP100

4.6

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.8

.;.;.;.;.;.;.;.;.;.;D;.;.

REVEL

Benign

0.28

Sift

Benign

0.056

.;.;.;.;.;.;.;.;.;.;T;.;.

Sift4G

Benign

0.21

T;T;D;T;T;T;T;D;D;D;T;D;D

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;D;.;.

Vest4

0.86

MutPred

0.59

Loss of MoRF binding (P = 0.2285);Loss of MoRF binding (P = 0.2285);.;Loss of MoRF binding (P = 0.2285);Loss of MoRF binding (P = 0.2285);Loss of MoRF binding (P = 0.2285);Loss of MoRF binding (P = 0.2285);.;.;.;Loss of MoRF binding (P = 0.2285);.;.;

MVP

0.83

MPC

0.0010

ClinPred

0.99

GERP RS

5.9

PromoterAI

-0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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